Methods and devices for monitoring the integrity of a fluid connection

ABSTRACT

A method of monitoring the integrity of a fluid connection between first and second fluid containing systems based on at least one time-dependent measurement signal from a pressure sensor in the first fluid containing system. The pressure sensor detects first pulses originating from a first pulse generator in the first fluid containing system and second pulses originating from a second pulse generator in the second fluid containing system. A parameter value representing a distribution of signal values within a time window is calculated by analyzing the measurement signal in the time domain and/or by using information on the timing of the second pulses in the measurement signal. The parameter value may be calculated as a statistical dispersion measure of the signal values, or from matching the signal to a predicted temporal signal profile of the second pulse. The integrity of the fluid connection is determined from the parameter value.

This application is a national phase application based onPCT/EP2009/004640 filed Jun. 26, 2009, which claims the benefit ofSwedish Patent Application No. SE 0801517-4, filed Jun. 26, 2008, andU.S. Provisional Application No. 61/075,774, filed Jun. 26, 2008, thecontents of all of which are incorporated herein by reference.

TECHNICAL FIELD

The present invention generally relates to monitoring of fluidconnections, and in particular to monitoring the integrity of a fluidconnection based on a pressure measurement. The present invention ise.g. applicable in arrangements for extracorporeal blood treatment.

BACKGROUND ART

In extracorporeal blood treatment, blood is taken out of a patient,treated and then reintroduced into the patient by means of anextracorporeal blood flow circuit. Generally, the blood is circulatedthrough the circuit by one or more pumping devices. The circuit isconnected to a blood vessel access of the patient, typically via one ormore access devices, such as needles or catheters, which are insertedinto the blood vessel access. Such extracorporeal blood treatmentsinclude hemodialysis, hemodiafiltration, hemofiltration, plasmapheresis,etc.

In extracorporeal blood treatment, it is vital to minimize the risk formalfunctions in the extracorporeal blood flow circuit, since these maylead to a potentially life-threatening condition of the patient. Seriousconditions may arise if the extracorporeal blood flow circuit isdisrupted, e.g. by an access device for blood extraction (e.g. anarterial needle/catheter) coming loose from the blood vessel access,causing air to be sucked into the circuit, or by an access device forblood reintroduction (e.g. a venous needle/catheter) coming loose fromthe blood vessel access, causing the patient to be drained of bloodwithin minutes. Other malfunctions may be caused by the blood vesselaccess becoming blocked or obstructed, or by the access device beingpositioned too close to the walls of the blood vessel access.

To this end, an apparatus for extracorporeal blood treatment may includeone or more surveillance devices that monitor the integrity of the bloodflow circuit and issue an alarm and/or cause appropriate action to betaken whenever a potentially dangerous situation is detected. Suchsurveillance devices may operate on measurement signals from one or morepressure sensors in the circuit. Conventionally, the monitoring iscarried out by comparing one or more measured average pressure levelswith one or more threshold values and/or by monitoring the presence ofair bubbles using an air detector in the circuit. For example, failurein the blood extraction may involve air being introduced into thecircuit, whereby the measured average pressure may approach atmosphericpressure, or the blood flow being blocked or obstructed, whereby themeasured average pressure may drop to a low level. A failure in thereintroduction of blood may be detectable as a decrease in the measuredaverage pressure. However, it may be difficult to set appropriatethreshold values, since the average pressure in the circuit may varybetween treatments, and also during a treatment, e.g. as a result of thepatient moving. Further, if an access device comes loose and gets stuckin bed sheets or the patient's clothes, the measured average pressuremight not change enough to indicate the potentially dangerous situation.

To increase the monitoring precision, WO 97/10013 proposes detecting, asone of several options, a heart signal in the measured pressure andusing the heart signal as an indicator of the integrity of a fluidconnection between an extracorporeal blood flow circuit and a bloodvessel access. The heart signal represents a pressure wave which isproduced by the patient's heart and transmitted from the patient'scirculatory system to the extracorporeal blood flow circuit via theblood vessel access. Malfunctions in the fluid connection will disturbthe transmission of the heart-generated pressure wave to the circuit,causing the heart signal to change or even disappear. The measuredpressure may also include a strong pressure wave produced by the bloodpump in the extracorporeal blood flow circuit. In WO 97/10013, themonitoring involves filtering a measured pressure signal to remove thefrequency components that originate from the blood pump, and thendetecting the heart signal by analysing the filtered pressure signal.The amplitude of the filtered pressure signal is then taken as anindication of the integrity of the fluid connection.

US2005/0010118 proposes a solution which involves applying a frequencyanalysis to a measured pressure signal to generate a frequency spectrum,removing a frequency component that originates from the blood pump, andidentifying a frequency component caused by the patient's heart.Anomalies of the blood vessel access are monitored based on theintensity level of the frequency component caused by the patient'sheart.

Corresponding needs to monitor the integrity of a fluid connectionbetween first and second fluid containing systems may arise in otherfields of technology.

SUMMARY OF THE INVENTION

It is an object of the invention to at least partly overcome one or moreof the above-identified limitations of the prior art. Specifically, itis an object to provide an alternative or complementary technique formonitoring the integrity of a fluid connection between first and secondfluid containing systems using a pressure measurement, preferably withan improved robustness and/or an increased certainty of detecting amalfunction in the fluid connection.

This and other objects, which will appear from the description below,are at least partly achieved by means of methods, devices, and acomputer program product according to the independent claims,embodiments thereof being defined by the dependent claims.

A first aspect of a first inventive concept of the invention is a methodfor monitoring the integrity of a fluid connection between first andsecond fluid containing systems based on at least one time-dependentmeasurement signal from at least one pressure sensor in the first fluidcontaining system, wherein the first fluid containing system comprises afirst pulse generator, and the second fluid containing system comprisesa second pulse generator, and wherein said at least one pressure sensoris arranged to detect first pulses originating from the first pulsegenerator and second pulses originating from the second pulse generator,said method comprising: receiving said at least one measurement signal;generating, based on said at least one measurement signal, atime-dependent monitoring signal in which the first pulses areessentially eliminated; calculating a parameter value based on signalvalues within a time window in the monitoring signal, the parametervalue representing a distribution of the signal values; and determiningthe integrity of the fluid connection based at least partly on theparameter value.

In one embodiment, said calculating comprises: calculating the parametervalue as a statistical dispersion measure of the signal values withinthe time window. The statistical dispersion measure may include at leastone of: a standard deviation, a variance, a coefficient of variation, asum of differences, an energy, a power, a sum of absolute deviationsfrom an average value, and an average of absolute differences from anaverage value.

In one embodiment, said calculating comprises: matching the signalvalues within the time window to a predicted temporal signal profile ofa second pulse. The parameter value may be a correlation value resultingfrom said matching.

In one embodiment, said calculating comprises: calculating across-correlation between the signal values within the time window andthe predicted temporal signal profile; and identifying a maximumcorrelation value in the cross-correlation; wherein said determiningcomprises: comparing the maximum correlation value to a threshold value.

In one embodiment, said calculating comprises: obtaining a time point ofthe maximum correlation value, and validating the maximum correlationvalue by comparing the time point to a predicted time point.

In one embodiment, the method further comprises the step of obtaining areference pressure signal from a reference sensor in the first fluidcontaining system, wherein the reference sensor is arranged to detectsaid second pulses even if the fluid connection is compromised, andcalculating the predicted temporal signal profile based on the referencepressure signal. Additionally, the method may further comprise the stepsof calculating a magnitude value indicative of the magnitude of thesecond pulses in the reference pressure signal, and comparing themagnitude value to a limit, wherein the step of calculating thepredicted temporal signal profile based on the reference pressure signalmay be conditioned upon said step of comparing. Alternatively oradditionally, the step of calculating the predicted temporal signalprofile may comprise adjusting for a difference in transit time betweenthe reference sensor and said at least one pressure sensor, wherein thedifference in transit time may be given by a predefined value, or may becalculated based on a difference in fluid pressure between the locationof the reference sensor and said at least one pressure sensor.

In one embodiment, the time window is selected so as to contain at leastone second pulse. The length of the time window may be chosen to exceeda maximum pulse repetition interval of the second pulse generator.

In one embodiment, the time window is chosen based on timing informationindicative of the timing of the second pulses in said at least onemeasurement signal.

In one embodiment, said monitoring signal is generated by: filteringsaid at least one measurement signal to remove the first pulses;deriving, based on timing information indicative of the timing of thesecond pulses in said at least one measurement signal, a set of signalsegments in the thus-filtered measurement signal(s); and aligning andadding the signal segments, based on the timing information, to generatesaid monitoring signal.

In one embodiment, said calculating comprises: identifying a candidatesecond pulse in the monitoring signal and a corresponding candidate timepoint; and validating the candidate second pulse based on the candidatetime point in relation to timing information indicative of the timing ofthe second pulses in said at least one measurement signal.

In one embodiment, the timing information is obtained from a pulsesensor coupled to the second fluid containing system.

In one embodiment, the timing information is obtained as a function ofthe relative timing of second pulses identified based on precedingparameter values.

In one embodiment, the first fluid containing system is anextracorporeal blood flow circuit comprising an arterial access device,a blood processing device, and a venous access device, wherein thesecond fluid containing system is a human blood system comprising ablood vessel access, wherein the arterial access device is connected tothe human blood system, wherein the venous access device is connected tothe blood vessel access to form the fluid connection, wherein the firstpulse generator is a pumping device arranged in the extracorporeal bloodflow circuit to pump blood from the arterial access device through theblood processing device to the venous access device, wherein said atleast one measurement signal comprises at least one venous measurementsignal derived from at least one venous pressure sensor locateddownstream of the pumping device, and at least one arterial measurementsignal derived from at least one arterial pressure sensor locatedupstream of the pumping device, and wherein the monitoring signal isgenerated based on said at least one venous measurement signal, saidmethod comprising: identifying at least one second pulse in said atleast one arterial measurement signal; and calculating the timinginformation from the thus-identified second pulse(s).

In one embodiment, the method further comprises: intermittently turningoff the first pulse generator; identifying at least one second pulse insaid at least one measurement signal; and calculating the timinginformation from the thus-identified second pulse.

In one embodiment, the method further comprises: identifying a set ofcandidate second pulses based on said at least one measurement signal;deriving a sequence of candidate time points based on the set ofcandidate second pulses; validating the sequence of candidate timepoints against a temporal criterion; and calculating the timinginformation as a function of the thus-validated sequence of candidatetime points.

In one embodiment, the first fluid containing system is anextracorporeal blood processing system comprising an access device,wherein the second fluid containing system is a human blood systemcomprising a blood vessel access, and wherein a connection between theaccess device and the blood vessel access forms the fluid connection.

A second aspect of the first inventive concept of the invention is acomputer program product comprising instructions for causing a computerto perform the method according to the first aspect.

A third aspect of the first inventive concept of the invention is adevice for monitoring the integrity of a fluid connection between firstand second fluid containing systems based on at least one time-dependentmeasurement signal from at least one pressure sensor in the first fluidcontaining system, wherein the first fluid containing system comprises afirst pulse generator, and the second fluid containing system comprisesa second pulse generator, and wherein said at least one pressure sensoris arranged to detect first pulses originating from the first pulsegenerator and second pulses originating from the second pulse generator,said device comprising: an input for said at least one measurementsignal; and a signal processor connected to said input and comprising aprocessing module configured to generate, based on said at least onemeasurement signal, a time-dependent monitoring signal in which thefirst pulses are essentially eliminated, and to calculate a parametervalue based on signal values within a time window in the monitoringsignal, the parameter value representing a distribution of the signalvalues, said signal processor being configured to determine theintegrity of the fluid connection based at least partly on the parametervalue.

A fourth aspect of the first inventive concept of the invention is adevice for monitoring the integrity of a fluid connection between firstand second fluid containing systems based on at least one time-dependentmeasurement signal from at least one pressure sensor in the first fluidcontaining system, wherein the first fluid containing system comprises afirst pulse generator, and the second fluid containing system comprisesa second pulse generator, and wherein said at least one pressure sensoris arranged to detect first pulses originating from the first pulsegenerator and second pulses originating from the second pulse generator,said device comprising: means for receiving said at least onemeasurement signal; means for generating, based on said at least onemeasurement signal, a time-dependent monitoring signal in which thefirst pulses are essentially eliminated; means for calculating aparameter value based on signal values within a time window in themonitoring signal, the parameter value representing a distribution ofthe signal values; and means for determining the integrity of the fluidconnection based at least partly on the parameter value.

Embodiments of the third and fourth aspects of the first inventiveconcept may correspond to the above-identified embodiments of the firstaspect of the first inventive concept.

A first aspect of a second inventive concept of the invention is amethod for monitoring the integrity of a fluid connection between firstand second fluid containing systems based on at least one time-dependentmeasurement signal from at least one pressure sensor in the first fluidcontaining system, wherein the first fluid containing system comprises afirst pulse generator, and the second fluid containing system comprisesa second pulse generator, and wherein said at least one pressure sensoris arranged to detect first pulses originating from the first pulsegenerator and second pulses originating from the second pulse generator,said method comprising: receiving said at least one measurement signal;obtaining timing information indicative of the timing of the secondpulses in said at least one measurement signal; processing said at leastone measurement signal based on the timing information, to calculate aparameter value indicative of presence or absence of the second pulses;and determining the integrity of the fluid connection based at leastpartly on the parameter value.

In one embodiment, said processing comprises: locating a time window inthe measurement signal, or a monitoring signal obtained therefrom, basedon the timing information; and calculating the parameter value based onthe signal values within said time window.

In one embodiment, said processing further comprises: selecting thelength of the time window based on the timing information.

In one embodiment, said processing comprises: generating atime-dependent monitoring signal by filtering said at least onemeasurement signal to remove the first pulses; wherein the parametervalue is calculated based on the monitoring signal.

In one embodiment, said generating further comprises: selecting a set ofsignal segments in the thus-filtered measurement signal(s); and aligningand adding the signal segments, based on the timing information, togenerate the monitoring signal.

In one embodiment, said calculating comprises: identifying a candidatesecond pulse in the monitoring signal and a corresponding candidate timepoint; and validating the candidate second pulse based on the candidatetime point in relation to the timing information.

In one embodiment, the timing information is obtained from a pulsesensor coupled to the second fluid containing system.

In one embodiment, the timing information is obtained as a function ofthe relative timing of second pulses identified based on precedingparameter values.

In one embodiment, the method further comprises the step of obtaining areference pressure signal from a reference sensor in the first fluidcontaining system, wherein the reference sensor is arranged to detectsaid second pulses even if the fluid connection is compromised, andwherein said step of obtaining the timing information comprises:identifying at least one second pulse in the reference pressure signaland obtaining an estimated difference in arrival time between thereference sensor and said at least one pressure sensor. The estimateddifference in arrival time may be given by a predefined value, or may becalculated based on a difference in fluid pressure between the locationof the reference sensor and said at least one pressure sensor.Additionally, the method may further comprise the steps of calculating amagnitude value indicative of the magnitude of said at least one secondpulse in the reference pressure signal, and comparing the magnitudevalue to a limit, wherein the step of obtaining an estimated differencein arrival time may be conditioned upon said step of comparing.

In one embodiment, the first fluid containing system is anextracorporeal blood flow circuit comprising an arterial access device,a blood processing device, and a venous access device, wherein thesecond fluid containing system is a human blood system comprising ablood vessel access, wherein the arterial access device is connected tothe human blood system, wherein the venous access device is connected tothe blood vessel access to form the fluid connection, wherein the firstpulse generator is a pumping device arranged in the extracorporeal bloodflow circuit to pump blood from the arterial access device through theblood processing device to the venous access device, wherein said atleast one measurement signal comprises at least one venous measurementsignal derived from at least one venous pressure sensor locateddownstream of the pumping device, and at least one arterial measurementsignal derived from at least one arterial pressure sensor locatedupstream of the pumping device, and wherein the monitoring signal isgenerated based on said at least one venous measurement signal, saidmethod comprising: identifying at least one second pulse in said atleast one arterial measurement signal; and calculating the timinginformation from the thus-identified second pulse(s).

In one embodiment, the method further comprises: intermittently turningoff the first pulse generator; identifying at least one second pulse insaid at least one measurement signal; and calculating the timinginformation from the thus-identified second pulse.

In one embodiment, the method further comprises: identifying a set ofcandidate second pulses based on said at least one measurement signal;deriving a sequence of candidate time points based on the set ofcandidate second pulses; validating the sequence of candidate timepoints against a temporal criterion; and calculating the timinginformation as a function of the thus-validated sequence of candidatetime points.

In one embodiment, said obtaining further comprises: identifying a setof candidate second pulses based on said at least one measurementsignal; deriving a sequence of candidate time points based on the set ofcandidate second pulses; generating a set of validated candidate secondpulses by validating the sequence of candidate time points against atemporal criterion; wherein said processing comprises: calculating a setof average representations, each average representation being formed byaligning and adding signal segments of said at least one measurementsignal that correspond to a unique combination of validated candidatesecond pulses; and calculating the parameter value for each of saidaverage representations; and wherein said determining comprisescomparing a maximum parameter value to a threshold value.

In one embodiment, the parameter value represents a distribution ofsignal values.

A second aspect of the second inventive concept of the invention is acomputer program product comprising instructions for causing a computerto perform the method according to the first aspect of the secondinventive concept.

A third aspect of the second inventive concept of the invention is adevice for monitoring the integrity of a fluid connection between firstand second fluid containing systems based on at least one time-dependentmeasurement signal from at least one pressure sensor in the first fluidcontaining system, wherein the first fluid containing system comprises afirst pulse generator, and the second fluid containing system comprisesa second pulse generator, and wherein said at least one pressure sensoris arranged to detect first pulses originating from the first pulsegenerator, and second pulses originating from the second pulsegenerator, said device comprising: an input for said at least onemeasurement signal; and a signal processor connected to said input andcomprising a processing module configured to obtain timing informationindicative of the timing of the second pulses in said at least onemeasurement signal, and to process said at least one measurement signalbased on the timing information so as to generate a parameter valueindicative of presence or absence of the second pulses, said signalprocessor being configured to determine the integrity of the fluidconnection based at least partly on the parameter value.

An fourth aspect of the second inventive concept of the invention is adevice for monitoring the integrity of a fluid connection between firstand second fluid containing systems based on at least one time-dependentmeasurement signal from at least one pressure sensor in the first fluidcontaining system, wherein the first fluid containing system comprises afirst pulse generator, and the second fluid containing system comprisesa second pulse generator, and wherein said at least one pressure sensoris arranged to detect first pulses originating from the first pulsegenerator, and second pulses originating from the second pulsegenerator, said device comprising: means for receiving said at least onemeasurement signal; means for obtaining timing information indicative ofthe timing of the second pulses in said at least one measurement signal;means for processing said at least one measurement signal based on thetiming information, to generate a parameter value indicative of presenceor absence of the second pulses, and means for determining the integrityof the fluid connection based at least partly on the parameter value.

Embodiments of the third and fourth aspects of the second inventiveconcept may correspond to the above-identified embodiments of the firstaspect of the second inventive concept.

Still other objectives, features, aspects and advantages of the presentinvention will appear from the following detailed description, from theattached claims as well as from the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the inventive concepts will now be described in moredetail with reference to the accompanying schematic drawings.

FIG. 1 is a schematic view of a general fluid arrangement in which theinventive concepts may be used for monitoring the integrity of a fluidconnection.

FIG. 2 is a flow chart of a monitoring process according to a firstinventive concept.

FIG. 3(a) is a plot of the measurement signal as a function of time,FIG. 3(b) is a plot of the measurement signal in FIG. 3(a) afterfiltering, and FIG. 3(c) illustrates a statistical dispersion measurecalculated for a sequence of time windows in the signal in FIG. 3(b).

FIG. 4(a) illustrates a matching procedure between a measurement signaland a predicted signal profile, FIG. 4(b) illustrates the position ofbest match, and FIG. 4(c) is a correlation curve resulting from thematching procedure in FIG. 4(a).

FIG. 5(a) is a plot of a signal segment containing a second pulse, andFIG. 5(b) is plot of an evaluation segment generated by averaging tensignal segments.

FIG. 6 is a flow chart of a monitoring process according to a secondinventive concept.

FIG. 7(a)-7(d) illustrate processing of candidate pulses identified in ameasurement signal.

FIG. 8 is a flow chart of part of a monitoring process according to thesecond inventive concept.

FIG. 9 is a flow chart of a monitoring process that combines the firstand second inventive concepts.

FIG. 10 is a schematic view of a system for hemodialysis treatmentincluding an extracorporeal blood flow circuit.

FIG. 11(a) is a plot in the time domain of a venous pressure signalcontaining both pump frequency components and a heart signal, and FIG.11(b) is a plot of the corresponding signal in the frequency domain.

FIG. 12 is a flow chart of an exemplifying monitoring process.

FIG. 13 is a block diagram of a data analyser for executing the processof FIG. 12.

FIGS. 14(a) and 14(b) are plots in the time domain of a pressure signalafter processing in a beating detection module in the data analyser ofFIG. 13, with and without a heart signal.

FIGS. 15(a) and 15(b) are enlarged view of the plots in FIGS. 14(a) and14(b).

FIGS. 16(a) and 16(b) are plots of envelopes extracted from the data inFIGS. 15(a) and 15(b).

FIG. 17 is a plot of the sum of derivatives as a function of time,calculated from envelopes with and without a heart signal.

FIG. 18 is a plot of variance as a function of time, calculated fromenvelopes with and without a heart signal.

FIG. 19 is a diagram illustrating the performance of a beating detectionmodule, for different relative magnitudes between the blood pulse andthe heart pulse.

FIG. 20 is a schematic view of an arrangement of analog devices fordetection of a beating component in a pressure signal.

DETAILED DESCRIPTION OF INVENTIVE CONCEPTS AND EMBODIMENTS

In the following, inventive concepts and associated embodiments will bedescribed with reference to fluid containing systems in general.Thereafter, the inventive concepts will be further exemplified in thecontext of systems for extracorporeal blood treatment.

Throughout the following description, like elements are designated bythe same reference signs.

General

FIG. 1 illustrates a general fluid arrangement in which a fluidconnection C is established between a first fluid containing system S1and a second fluid containing system S2. The fluid connection C may ormay not transfer fluid from one system to the other. A first pulsegenerator 3 is arranged to generate a series of pressure waves in thefluid within the first system S1, and a second pulse generator 3′ isarranged to generate a series of pressure waves in the fluid within thesecond system S2. A pressure sensor 4 c is arranged to measure the fluidpressure in the first system S1. As long as the fluid connection C isintact, pressure waves generated by the second pulse generator 3′ willtravel from the second system S2 to the first system S1, and thus secondpulses originating from the second pulse generator 3′ will be detectedby the pressure sensor 4 c in addition to first pulses originating fromthe first pulse generator 3. It is to be noted that either one of thefirst and second pulse generators 3, 3′ may include more than onepulse-generating device. Further, any such pulse-generating device mayor may not be part of the respective fluid containing system S1, S2.

The fluid arrangement of FIG. 1 further includes a surveillance device25 which is connected to the pressure sensor 4 c, and possibly to one ormore further pressure sensors 4 a, 4 b, as indicated in FIG. 1. Thereby,the surveillance device 25 acquires one or more measurement signals thatare time-dependent to provide a real time representation of the fluidpressure in the first system S1. The surveillance device 25 monitors theintegrity of the fluid connection C, based on the principle that thepresence of second pulses indicates that the fluid connection C isintact, whereas absence of second pulses indicates that the fluidconnection C is compromised. The absence of second pulses may bring thesurveillance device 25 to issue an alarm or warning signal, and/or alerta control system of the first or second fluid containing systems S1, S2to take appropriate action.

The surveillance device 25 is thus configured to continuously processthe time-dependent measurement signal(s) to determine whether secondpulses are present or not. Typically, the determination involvesanalyzing the measurement signal(s), or a pre-processed version thereof,in the time domain to calculate a value of an evaluation parameter whichis indicative of the presence or absence of second pulses in themeasurement signal(s). Depending on implementation, the surveillancedevice 25 may use digital components or analog components, or acombination thereof, for receiving and processing the measurementsignal(s).

In the context of the present disclosure, “absence” of a pulse may implythat the pulse has disappeared, or at least that it has decreasedsufficiently in magnitude compared to the pulse deemed to be “present”.The assessment of presence or absence may involve calculating anevaluation parameter value based on the measurement signal(s) andcomparing the parameter value to a threshold value.

First Inventive Concept

FIG. 2 is a flow chart that illustrates steps of a monitoring processaccording to a first inventive concept. A measurement signal is received(step 201) and subjected to a filtering process (step 202) thatessentially removes the first pulses from the measurement signal, whileleaving at least part of the second pulses intact. The filteredmeasurement signal is then subjected to a time domain analysis (step203), in which a value of an evaluation parameter is calculated based onsignal values within a time window in the filtered measurement signal,which is denoted “evaluation segment” in the following. The calculationis typically designed such that the evaluation parameter represents thedistribution of signal values within the evaluation segment. Based onthe resulting value of the evaluation parameter, it is decided (step204) whether the fluid connection is intact or not, typically bycomparing the resulting value to a threshold value.

For continuous surveillance, a time sequence of evaluation parametervalues is calculated based on a time sequence of evaluation segmentsobtained from the measurement signal. These evaluation segments may beoverlapping or non-overlapping in time. In one embodiment, individualsections of the measurement signal are acquired, filtered and analyzed,one after the other. Each evaluation segment may correspond to one suchsection of the measurement signal; the time window is thus appliedalready when the measurement signal is acquired. In another embodiment,the measurement signal is continuously acquired and filtered, whereuponevaluation segments are extracted from the filtered signal and analyzed.

FIG. 3(a) shows an example of a time-dependent measurement signalcontaining first and second pulses with a relative magnitude of 10:1.The first and second pulses have a frequency of 1 Hz and 1.33 Hz,respectively. FIG. 3(b) shows the time-dependent measurement signalafter removal of the first pulses, leaving only second pulses and noise.It should be noted that there is an absence of second pulses after about4 seconds. FIG. 3(c) illustrates a variance measure calculated for asequence of non-overlapping time windows in the filtered measurementsignal in FIG. 3(b), each time window being about 0.75 seconds. Clearly,by using the variance measure as an evaluation parameter, it is possibleto detect the absence of the second pulse at the time point of about 4seconds. An exemplifying threshold value is indicated by a dotted line.

The first inventive concept has the potential of providing acomparatively robust measure of the integrity of the fluid connection C.By analyzing the temporal distribution of signal values within theevaluation segment, an improved tolerance to noise and disturbingsignals may be obtained.

Furthermore, compared to techniques that rely on frequency domainanalysis of the measurement signal for detecting the presence of secondpulses, the first inventive concept may provide an improved tolerance tovariations in the pulse repetition interval of the second pulsegenerator 3′, since the first inventive concept relies on a time domainanalysis. Such variations may occur, e.g., when the second pulsegenerator 3′ is a human heart, and the second system S2 thus is theblood system of a human. Variations in heart rhythm (heart ratevariability, HRV) will cause the peak from the heart in the frequencydomain to be smeared out, making it harder to detect. In healthysubjects under calm conditions, HRV may be as large as 15%. Unhealthysubjects may suffer from severe heart conditions such as atrialfibrillation and supraventricular ectopic beating, which may lead to anHRV in excess of 20%, and ventricular ectopic beating, for which HRV maybe in excess of 60%. These heart conditions are not uncommon among,e.g., dialysis patients.

As long as the time window is selected such that each evaluation segmentcontains at least one second pulse, the presence/absence of secondpulses will affect the evaluation parameter, if properly chosen. Afixed-length time window may be used, with the length of the time windowbeing chosen with respect to a maximum pulse repetition rate of thesecond pulse generator 3′. The length of the time window may be set byconstraints in the second pulse generator 3′ or by a selectedperformance limit of the surveillance method. Alternatively, the lengthof the time window and/or the location of the time window in thefiltered measurement signal may be selected based on a predicted timingof the second pulse(s) to be detected. The acquisition and use of such apredicted timing (“timing information”) will be further exemplifiedbelow with reference to the second inventive concept.

Still further, the time domain analysis according to the first inventiveconcept may allow for faster detection than a frequency domain analysis,since the former may have the ability to detect a single second pulse inthe evaluation segment whereas the generation of a frequency spectrumrequires a greater number of second pulses in the evaluation segment.Thus, frequency domain analysis may be associated with a greater timelag than time domain analysis.

The evaluation parameter may be calculated as a statistical dispersionmeasure of the signal values within the evaluation segment. Non-limitingexamples of potentially useful statistical dispersion measures includestandard deviation (σ), variance (σ²), coefficient of variation (σ/μ)and variance-to-mean (ρ²/μ). Other examples include a sum ofdifferences, e.g. given by

${\sum\limits_{i = 2}^{n}\;{{x_{i} - x_{i - 1}}}},{{or}\mspace{14mu}{\sum\limits_{i = 1}^{n}{\sum\limits_{j = 1}^{n}{{x_{i} - x_{j}}}}}},$

or an energy measure, such as

${\sum\limits_{i = 1}^{n}x_{i}^{2}},$

with n being the number of signal values x in the evaluation segment.Yet other examples include a measure based on a sum of absolutedifferences from an average value m, with the average value m beingcalculated for the signal values in the evaluation segment using anysuitable function, such as arithmetic mean, geometric mean, median, etc.It is to be noted that all of the above suggested dispersion measuresalso include normalized and/or weighted variants thereof.

As an alternative or supplement to calculating a statistical dispersionmeasure, the evaluation parameter may result from a matching procedure,in which the evaluation segment is matched to one or more predictedsignal profiles of a second pulse. Preferably, but not necessarily, eachpredicted signal profile represents a single second pulse. Typically,the matching procedure involves convolving or cross-correlating theevaluation segment and the predicted signal profile, and the evaluationparameter value is a resulting correlation value, typically the maximumcorrelation value.

A matching procedure based on cross-correlation is further exemplifiedin FIGS. 4(a)-4(c). The matching procedure is used to distinguishbetween the hypothesesH ₀ : x(n)=w(n)H ₁ : x(n)=s(n)+w(n)

with x(n) being the evaluation segment, w(n) being an error signalrepresenting disturbances introduced by noise/signalinterference/measurement errors, etc, and s(n) being the predictedsignal profile of the second pulse. If H₁ is deemed more likely than H₀,then a second pulse has been identified and the fluid connection C isdeemed intact. If H₀ is deemed more likely than H₁, then a second pulsecannot be identified and the fluid connection C may be compromised.

FIG. 4(a) is a graph showing an example of a predicted signal profiles(n) and an evaluation segment x(n). In this particular example, theevaluation segment has a signal-to-noise ratio (SNR) of 4.8 dB, i.e. theenergy of the signal profile s(n) is 3 times the energy of the errorsignal w(n). During the cross-correlation, the signal profile s(n) isslid in a number of time steps along the time axis, as indicated byarrow in FIG. 4(a), and the integral of the product s(n)·x(n) iscalculated for each time step. The cross-correlation thus results in atime sequence of correlation values, with the maximum correlation valueindicating the time point of best match between x(n) and s(n). FIG. 4(b)illustrates the relative position between x(n) and s(n) at the timepoint for best match, and FIG. 4(c) illustrates the resultingcorrelation values as a function of said time steps. The magnitude ofthe maximum correlation value, optionally calculated as a weightedaverage within a range around the maximum correlation value (c_(max)),may thus be used to distinguish between the above hypotheses.

As indicated in FIG. 4(c), the matching procedure not only identifiesthe presence of a second pulse, it also provides an indication of thelocation of the second pulse in the evaluation segment, given by thetime point (t_(p)) for the maximum correlation value (c_(max)). Thistime point may be used to assess the reliability of the determinedmaximum correlation value, by comparing this time point to a predictedtime point. Such a predicted time point may be obtained from aforesaidtiming information, as will be further explained below in relation tothe second inventive concept.

The predicted signal profile may be generated as an average of a numberof recordings of second pulses. For example, it may be generated byaveraging a number of evaluation segments, before and/or during themonitoring process.

To improve the signal quality of the predicted profile, with or withoutaveraging, the measurement signal may be acquired while the first pulsegenerator is stopped, whereby the measurement signal is free of firstpulses. Thus, the first pulse generator may be intermittently stoppedduring the monitoring process for calculation of an updated signalprofile of the second pulses.

In another variant, the predicted signal profile is obtained from one ormore reference signals originating from a reference pressure sensor(e.g. any one of pressure sensors 4 a-4 c in FIG. 1) in the firstsystem. Such a reference pressure sensor is suitably arranged to detectsecond pulses even if the fluid connection is compromised, e.g. via asecond fluid connection between the first and second fluid containingsystems. The reference pressure sensor may be installed to be isolatedfrom the first pulses, such that the reference signal is essentiallyfree of first pulses. Alternatively, if the reference signal includesboth first and second pulses, the reference signal may be subjected to afiltering process (e.g. according to step 202 in FIG. 2) to remove thefirst pulses while leaving the second pulses intact in the referencesignal. An example of such a reference pressure sensor is an arterialpressure sensor in an extracorporeal blood flow circuit, to be furtherdescribed below. In such an extracorporeal blood flow circuit, themeasurement signal(s) may originate from one or more venous pressuresensors, e.g. if the monitoring process aims at monitoring the integrityof the venous-side fluid connection between the extracorporeal bloodflow circuit and a patient.

In one specific implementation, the reference signal is obtainedcontinuously or intermittently during the monitoring process, and thepredicted signal profile is continuously or intermittently calculatedbased on the reference signal. Thus, in the context of theabove-mentioned extracorporeal blood flow circuit, the integrity of thevenous-side fluid connection may be monitored by continuously matchingevaluation segments from the venous pressure sensor against a predictedsignal profile obtained from the arterial pressure sensor. It is evenconceivable that the predicted signal profile is updated for eachevaluation segment (denoted “synchronous monitoring” in the following).The matching procedure may benefit from the use of timing information,as will be further explained below in relation to the second inventiveconcept. Alternatively, the predicted signal profile may bepre-generated, e.g. by averaging recordings of second pulses from anumber of fluid arrangements, similar to the one that is being monitored(cf. FIG. 1). Optionally, such a pre-generated signal profile may beadapted to specifics of the fluid arrangement to be monitored, byapplying a mathematical model taking into account arrangement-specificparameters, such a type of fluid connection, flow rate, fluidcharacteristics, etc. Alternatively, the predicted signal profile may beobtained entirely by mathematical modeling based on arrangement-specificparameters. According to yet another alternative, a standard profile isused as predicted signal profile, e.g. a bell-shaped function such as aGaussian distribution function.

In order to improve the detection of second pulses, it is conceivable tosubject the filtered measurement signal/evaluation segment to a signalenhancement process, which removes high-frequency components (cf. errorsignal w(n)), before calculation of the evaluation parameter value. Sucha signal enhancement process may involve subjecting the filteredmeasurement signal/evaluation segment to a low-pass filtering. However,a more significant improvement in SNR of the evaluation segment may beachieved by averaging several consecutive second pulses in the filteredmeasurement signal, again based on the above-mentioned predicted timingof the second pulse(s) (i.e. timing information). Such a signalenhancement process would thus involve using the predicted timing toidentify a set of second pulse segments in the filtered measurementsignal, aligning the second pulse segments in the time domain based onthe predicted timing, and generating an average representation bysumming the aligned signal values for each time value in the timedomain. Optionally, the average representation is normalized by thenumber of second pulse segments to generate a true average. The averagerepresentation may then be used as the above-mentioned evaluationsegment, or the evaluation segment may be extracted from a time windowwithin the average representation.

The signal enhancement process is further exemplified in FIGS.5(a)-5(b). FIG. 5(a) is a time domain representation of a filteredmeasurement signal x(n)=s(n)+w(n) with a SNR of −9 dB, i.e. the energyof the error signal w(n) is 8 times the energy of the signal profiles(n), making time domain analysis for detection of the second pulsedifficult, if not impossible. FIG. 5(b) is a time domain representationafter averaging of 10 different second pulse segments similar to the onein FIG. 5(a). Clearly, the SNR has been improved significantly, allowinga second pulse to be detected using time domain analysis.

It is to be understood that the monitoring process of FIG. 2 may operateon more than one measurement signal, if the fluid arrangement to bemonitored includes more than one pressure sensor (cf. 4 a, 4 b in FIG.1). In such a configuration, the above-described signal enhancementprocess may involve using aforesaid timing information to identify andaverage second pulse segments from at least two filtered measurementsignals originating from different pressure sensors. Thus, the secondpulse segments may be extracted from plural time windows in eachmeasurement signal, and/or from one or more time windows in differentmeasurement signals.

The filtering process according to step 202 in FIG. 2 aims at removingthe first pulses from the measurement signal to such an extent that thesecond pulses can be detected by the subsequent time domain analysis(step 203). For example, a comb filter and/or a combination of band-stopor notch filters, typically cascade coupled, may be operated on themeasurement signal to block out all frequency components originatingfrom the first pulse generator 3. Alternatively, such blocking may beachieved by the use of one or more adaptive filters and notch-equivalentfilters, e.g. as disclosed in aforesaid WO 97/10013. In yet anotheralternative embodiment, the measurement signal is processed in the timedomain to cancel the first pulses. In such an embodiment, a standardsignal profile of the first pulses may be obtained, which is thensubtracted from the measurement signal at suitable amplitude and phase.The phase is indicated by phase information which may be obtained from asignal generated by a phase sensor coupled to the first pulse generator3, or from a control signal for the first pulse generator 3. Thestandard signal profile may be obtained from one or more of the pressuresensors 4 a-4 c in the first fluid containing circuit S1, suitably byidentifying and averaging a set of first pulse segments in themeasurement signal(s) similarly to the above-mentioned signalenhancement process. The standard signal profile may or may not beupdated intermittently during the monitoring process. Alternatively, apredetermined standard signal profile is used, which optionally may bemodified according to a mathematical model accounting for wear in thefirst pulse generator, fluid flow rates, tubing dimensions, speed ofsound in the fluid, etc. It should be noted that by filtering themeasurement signal in the time domain, instead of the frequency domain,it is possible to eliminate the first pulses and still retain the secondpulses, even if the first and second pulses overlap in the frequencydomain.

Second Inventive Concept

FIG. 6 is a flow chart that illustrates steps of a monitoring processaccording to a second inventive concept. In this process, a measurementsignal is received (step 601) and timing information is obtained, fromthe measurement signal or otherwise (step 602). The timing informationis indicative of the timing of second pulses in the measurement signal.Subsequently, the measurement signal is processed (step 603) based onthe timing information, to calculate a value of an evaluation parameterwhich is indicative of the presence or absence of a second pulse in themeasurement signal. Based on the resulting value of the evaluationparameter, it is decided (step 604) whether the fluid connection isintact or not, typically by comparing the resulting value to a thresholdvalue.

Thus, in the second inventive concept, timing information indicates theexpected position of a second pulse in the measurement signal. Thisadditional information may allow the second pulse to be identified fromother types of signal features, e.g. different/simpler evaluationparameters, and/or it may allow for an increased reliability indetecting presence/absence of second pulses.

Furthermore, as explained above, the provision of timing informationallows for signal enhancement by identifying and averaging second pulsesegments in one or more measurement signals. The signal enhancement mayincrease the SNR of the measurement signal, allowing for the use of arudimentary measure as evaluation parameter, such as signal amplitude,local maximum, local average, etc. This may serve to improve theprocessing speed and/or allow for less sophisticated detectionequipment.

It is to be understood that the second inventive concept can be combinedwith any of the features of the first inventive concept. For example,the measurement signal may be filtered to remove first pulses, and theevaluation parameter may be calculated for an evaluation segment givenby signal values within a time window in the filtered measurementsignal. Also, any one of the evaluation parameters suggested in relationto the first inventive concept is equally applicable to the secondinventive concept. It is to be noted, however, that the filtering of themeasurement signal is not an essential feature of the second inventiveconcept, since the use of timing information may allow second pulses tobe detected in the measurement signal even in the presence of firstpulses.

The second inventive concept may also improve the detection speed, sincethe timing information may provide a predicted time point for the secondpulse in the measurement signal/filtered measurement signal/evaluationsegment. Thereby, the number of signal values that need to be processedfor calculation of the evaluation parameter value may be reduced. Forexample, the aforesaid matching procedure may be simplified, since thecorrelation between the predicted signal profile and the evaluationsegment need only be calculated for the predicted time point, or aconfined time range around this predicted time point. Correspondingly,the calculation of a statistical dispersion measure or theabove-mentioned rudimentary measure may be simplified, since theprovision of timing information makes it possible to reduce the size ofthe time window for extracting the evaluation segment, while stillensuring that each evaluation segment includes at least one secondpulse. For example, the size of the time window may be reduced if thetiming information indicates a shortened pulse interval between thesecond pulses, and/or the time window may be centered on the predictedtime point of each second pulse.

Still further, the second inventive concept allows for assessing thereliability of a calculated evaluation parameter value, by comparing atime point associated with the evaluation parameter value with apredicted time point given by the timing information. For example, thetime point for a maximum correlation value obtained in the aforesaidmatching procedure may be compared with a predicted time point for asecond pulse. If these time points deviate too much, the monitoringprocess may determine that a second pulse is absent, even though themagnitude of the correlation value might indicate presence of a secondpulse.

The timing information may be obtained in any one of a plurality ofdifferent ways. For example, the timing information may be extractedfrom the output signal of a pulse sensor coupled to the second fluidcontaining system. The output signal may indicate individual secondpulses or an average time between second pulses. In either case, apredicted time point for a second pulse in the measurement signal can becalculated based on the output signal of the pulse sensor and a knowndifference in arrival time between the pulse sensor and the pressuresensor(s) that generates the measurement signal(s). The pulse sensor maysense the pressure waves that are generated in the fluid by second pulsegenerator, or it may directly reflect the pulse generation process inthe second pulse generator, e.g. via a control signal for the secondpulse generator or a pulse rate meter mechanically coupled to the secondpulse generator. In one application, to be further exemplified below,the second fluid containing system is a blood system of a human, and thepulse generator is a human heart. In such an application, the timinginformation may be provided by any conventional pulse sensor such as apulse watch, a pulse oximeter, an electrocardiograph, etc.

Alternatively, the timing information may be obtained based on therelative timing of previously detected second pulses in the measurementsignal, e.g. given by the time points associated with previouslycalculated evaluation parameter values. For example, the time differencebetween the two most recently detected second pulses may be used topredict the time point for subsequent second pulse(s).

Alternatively, the timing information may be obtained from one or morereference signals originating from a reference pressure sensor in thefirst system. Such a reference pressure sensor is suitably arranged todetect second pulses even if the fluid connection is compromised, e.g.via a second fluid connection between the first and second fluidcontaining systems.

An example of such a reference pressure sensor is an arterial pressuresensor in an extracorporeal blood flow circuit, to be further describedbelow. In such an extracorporeal blood flow circuit, the measurementsignal(s) may originate from one or more venous pressure sensors, e.g.if the monitoring process aims at monitoring the integrity of thevenous-side fluid connection between the extracorporeal blood flowcircuit and a patient. The reference signal may be processed fordetection of at least one second pulse, using any suitable technique,including the time domain techniques disclosed herein. The time point ofthe detected second pulse in the reference signal can then be convertedto a predicted time point in the measurement signal/filtered measurementsignal/evaluation segment using a known/measured difference in pulsearrival/transit time between the reference sensor and the pressuresensor(s) used for monitoring. Thus, in one embodiment, the differencein transit time is given by a fixed and predefined value.

In another embodiment, the difference in transit time between a bloodline on the arterial side and a blood line on the venous side in theextracorporeal blood flow circuit is determined based on the actualarterial and venous pressures (absolute, relative, or average), whichmay be derived from any suitable sensor in the extracorporeal blood flowcircuit (including the venous and arterial pressure sensors). Thetransit time decreases if the pressure increases, i.e., high pressureequals short transit time. During operation of the extracorporeal bloodflow circuit, the venous pressure should be higher than the arterialpressure, and thus the transit time should be shorter in the venousblood line compared to the transit time in the arterial blood line. Thedifference in transit time may be determined based on, e.g., a physicalmodel or a look-up table. The model/table may not only includeinformation about pressure (absolute, relative, or average), but alsoinformation about material (elasticity, plasticity, etc), geometry(length, diameter, wall thickness, etc), temperature (both fluids andambient temperature), mechanical factors (clamp, tension, actuators,kinking/occlusion, etc), fluid properties (viscosity, water/blood,chemical composition, etc), etc. The thus-determined difference intransit time may then be used to relate a time point of a detectedsecond pulse in the reference signal from the arterial pressure sensorto a predicted time point in the measurement signal/filtered measurementsignal/evaluation segment originating from the venous pressure sensor.

In a variant, an improved estimation of the timing information may beobtained by aligning and adding the filtered measurementsignal/evaluation segment (derived from the venous pressure signal) witha correspondingly filtered reference signal (derived from the arterialpressure signal), to thereby calculate an average time-dependent signalwith improved SNR. The aligning may be based on the aforesaid differencein transit time, given by the actual arterial and venous pressures(absolute, relative, or average). By identifying one or more secondpulse(s) in the average time-dependent signal, an improved estimation ofthe timing information is obtained.

Alternatively or additionally, to potentially improve the precision ofthe timing information, the timing information may be obtained byintermittently stopping the first pulse generator, while identifying atleast one second pulse in the reference signal or the measurementsignal.

Optionally, the process of obtaining timing information based on anidentified second pulse, be it in the reference signal or themeasurement signal, may involve validating the identified second pulse(a candidate pulse) against a temporal criterion. Such a temporalcriterion may, e.g., indicate an upper limit and/or a lower limit forthe time difference between the time point for the candidate pulse andone or more previously identified (and suitably validated) secondpulses. These limits may be fixed, or they may be set dynamically inrelation to a preceding time difference. Any candidate pulse thatviolates the temporal criterion may be removed/discarded from use inobtaining the timing information.

In yet another alternative, the timing information is obtained from ameasurement signal using an iterative approach. In this iterativeapproach, the measurement signal is processed to calculate atime-sequence of evaluation parameter values, e.g. based on the firstinventive concept. These evaluation parameter values identify a sequenceof candidate pulses and associated candidate time points, which isvalidated against a temporal criterion. Such a temporal criterion may,e.g., indicate an upper limit and/or a lower limit for the timedifference between the candidate time points. The temporal criterion maybe given by constraints in the second pulse generator 3′. Any candidatetime points that violate the temporal criterion may beremoved/discarded, and the timing information may be obtained from theremaining time points.

Different validation methods may be used depending on the availabilityof previous timing information, i.e. information about time points ofpreceding second pulses. Such previous timing information may be givenby any one of the methods described in the foregoing, or resulting froma previous iteration of the iterative approach.

FIG. 7(a) illustrates a sequence of candidate pulses (denoted by X), aswell as a sequence of preceding second pulses (denoted by Y), laid outon a time axis. In a first validation step, predicted time points(arrows ↓ in FIG. 7(b)) are calculated based on the previous timinginformation (e.g. second pulses Y). In a second validation step, a firsttemporal criterion is applied to remove/discard any candidate pulsesthat lie too far from the predicted time points, as also shown in FIG.7(b). In a third validation step, a second temporal criterion is appliedto retain only the candidate pulse with the largest evaluation parametervalue among any candidate pulses that lie too close to each other, asshown in FIG. 7(c).

A different validation method may be used if previous timing informationis not available. FIG. 8 is a flow chart for such a validation method.The initial step 801 of identifying candidate pulses is followed by afirst validation step 802, in which a first temporal criterion isapplied to retain only the candidate pulse with the largest evaluationparameter value among any candidate pulses that lie too close to eachother. FIG. 7(d) shows an exemplifying result of applying the firstvalidation step 802 to the sequence of candidate pulses in FIG. 7(a).Then, in step 803, different combinations of the remaining candidatepulses are formed. In step 804, an average representation is calculatedfor each such combination, by aligning and summing corresponding signalsegments of the measurement signal/filtered measurement signal. Thecombinations may be formed based on a second temporal criterion thatdefines an upper limit and/or a lower limit for the time differencebetween the candidate pulses. In a second validation step 805, anevaluation parameter value is calculated for each such averagerepresentation, and the maximum evaluation parameter value is extracted.Finally, in step 806, it is decided whether the fluid connection isintact or not, by comparing the maximum evaluation parameter value to athreshold value. If the maximum evaluation parameter value exceeds thethreshold value, it may be concluded that a second pulse is present andthat the fluid connection is intact. It may be noted that there is noneed to explicitly extract the timing information in the validationmethod in FIG. 8, since the use of the timing information is embedded inthe final step 806 of determining the integrity of the fluid connection.

It should also be noted that different evaluation parameters and/orthreshold values may be used in steps 801 and 806. It is alsoconceivable to use a combination of two or more of the above alternativemethods for obtaining the timing information.

FIG. 9 is a flow chart of an embodiment that combines features of thefirst and second inventive concepts. Specifically, a measurement signalis obtained and filtered according to steps 201 and 202 of the firstinventive concept. Then, in step 202′, the filtered measurement signalis processed for signal enhancement, based on timing information. Asdiscussed above in relation to FIG. 5, step 202′ typically involvesidentifying, aligning and summing a set of second pulse segments in thefiltered measurement signal, to create an average signal representation.An evaluation parameter value is then calculated based on the enhancedsignal representation according to step 203/603 of the first/secondinventive concept, and it is decided whether the fluid connection isintact or not (steps 204/604). The method also involves receiving ameasurement signal (which may be the same measurement signal as in step201, or the aforesaid reference signal) according to step 601 of thesecond inventive concept. Then, the measurement/reference signal isfiltered to remove the first pulse, if required, according to step 202of the first inventive concept. Finally, the timing information isobtained according to step 602 of the second inventive concept.

Combinations of Monitoring Techniques

As explained in the foregoing, the technique for monitoring theintegrity of the fluid connection can be based on either of the firstand second inventive concepts, or a combination thereof. It is alsopossible to combine such an inventive monitoring technique with one ormore conventional monitoring techniques, which e.g. involve the use ofan air detector, or a comparison of average pressure levels withthreshold values as described by way of introduction. Other conventionalmonitoring techniques are disclosed in aforesaid WO 97/10013 andUS2005/0010118.

It might also be desirable to combine the inventive monitoringtechniques with other techniques that are specially designed to handleadverse operating conditions. One such operating condition may arisewhen the first and second pulses overlap in the frequency domain. Asdiscussed above in relation to step 202 of FIG. 2, such an operatingcondition could be handled by filtering the measurement signal in thetime domain. However, the monitoring precision may be increased furtherby combining the inventive monitoring technique with a phase-lockingtechnique or a beating detection method, to be described in thefollowing.

The phase-locking technique involves controlling the first/second pulsegenerator 3, 3′ so as to synchronize the pulse rate of the first andsecond pulse generators 3, 3′ while applying a phase difference betweenthe first and second pulses. Thereby, the first and second pulses willbe separated in time, and can be detected using the time domain analysisaccording to the first and/or second inventive concepts. The phasedifference may be approximately 180°, since this may maximize theseparation of the first and second pulses in the time domain. Thephase-locking technique may be activated when it is detected that thefrequency of the second pulse generator approaches a frequency of thefirst pulse generator, or vice versa.

The beating detection method is an alternative or complementarymonitoring technique which involves evaluating the presence or absenceof a beating signal in the measurement signal to determine the integrityof the fluid connection. The beating signal manifests itself as anamplitude modulation of the measurement signal and is formed byinterference between pressure waves generated by the first pulsegenerator and pressure waves generated by the second pulse generator.Instead of trying to identify second pulses in the measurement signal,the presence of second pulses is identified via the secondary effect ofbeating. Generally, beating is a phenomenon which is especiallynoticeable when two signals with closely spaced frequencies are addedtogether. Thus, the beating signal detection is inherently well-suitedto be used when the first and second pulses are closely spaced in thefrequency domain. The beating signal may or may not be detected byanalysing the measurement signal in the time domain. Suitably, thebeating detection involves obtaining one or more specific frequenciesrelated to the first pulse generator, and creating at least one filteredmeasurement signal in which all but one of said specific frequencies areremoved. The beating signal may then be detected by determining anenvelope of the filtered measurement signal. The beating detectionmethod is the subject of Applicant's co-pending Swedish patentapplication No. 0800890-6 and U.S. provisional patent application No.61/045,642, both filed on Apr. 17, 2008.

It is to be understood that in any one of the above combinations, thedifferent monitoring techniques may be carried out in series, in anyorder, or in parallel.

Performance Improvements

The performance of the different methods for monitoring the integrity ofa fluid connection as described herein may be improved by applying anyof the following variations.

Hypothesis Test

The determination of the integrity of the fluid connection between thefirst and second fluid containing systems could be represented by ahypothesis test. In this hypothesis test, the above-mentioned evaluationparameter value β is compared to a threshold. The output of thehypothesis is a decision, which may be “intact fluid connection” (H₁) ifβ>γ₁, “compromised fluid connection” (H₀) if β<γ₀, or “uncertaindecision” if γ₀≦β≦γ₁, wherein γ₀ and γ₁ are different thresholds.

Magnitude Dependent Monitoring Technique

The monitoring technique may be dynamically adjusted based on themagnitude of the first and/or second pulses in the measurement signaland/or in the reference signal. The dynamic adjustment may affect theprocess for obtaining timing information and/or the process forobtaining the parameter value based on the measurement signal.

For example, if the magnitude (e.g. amplitude) of second pulses in thereference signal are found to be smaller than the magnitude (e.g.amplitude) of second pulses in the measurement signal, or smaller than apredetermined absolute limit, the timing information may be obtainedbased on the measurement signal, whereas the timing informationotherwise is obtained based on the reference signal (or vice versa).Thus, with reference to FIG. 9, step 601 is adjusted based on themagnitude of second pulses.

In another example, if the magnitude (amplitude) of the second pulses inthe reference signal again are found to be too small, the monitoringmethod may switch to another method for detecting presence or absence ofsecond pulses in the measurement signal, e.g. a method that operateswithout timing information (e.g. by omitting steps 601, 602, 202 and202′ in FIG. 9).

In the above examples, if the magnitude of first and second pulses arecovariant entities, the dynamic adjustment may alternatively be based onthe magnitude of first pulses, or the magnitude of a combination offirst and second pulses.

Monitoring Technique Based on Patient Data Records

When the second fluid containing system (S2 in FIG. 1) is a blood systemof a patient, the monitoring method may be configured to access and usepatient-specific information, i.e. existing data records for thepatient, e.g. obtained in earlier treatments of the same patient. Thepatient-specific information may be stored in an internal memory of thesurveillance device (25 in FIG. 1), on an external memory which is madeaccessible to the surveillance device, or on a patient card where theinformation is e.g. transmitted wirelessly to the surveillance device,e.g. by RFID (Radio Frequency IDentification). For example, thesurveillance device may compare the filtered measurement signal, or aparameter derived therefrom, to the patient-specific information. Iflarge differences are identified, a warning may be issued and/or themonitoring technique may be modified (or chosen according to apredetermined table). Furthermore, the patient-specific information maybe used by the surveillance device to optimize the monitoring techniqueby e.g. determining personal threshold values for use in the foregoingalgorithms/processes. The patient-specific information may also be usedby the surveillance device to determine if an alternative monitoringtechnique or combinations of monitoring techniques should be used.

Use of Information from Regular Stops of First Pulse Generator

In one embodiment, the first pulse generator is regularly(intermittently or periodically) stopped, and the measurement signaland/or reference signal is analysed for determination of amplitude,frequency and phase of second pulses. This resulting information maythen be used to achieve detection by the above-mentioned phase-lockingtechnique.

Alternatively or additionally, if the magnitude (e.g. amplitude) of thesecond pulse(s) detected during such a stop is smaller than a certainlimit (chosen with a margin for safe detection), an alert on “uncertaindetection” may be issued. Alternatively, if the magnitude is smallerthan another limit, the first pulse generator may be actively controlledto be stopped at specific time intervals, where the information obtainedduring each stop may be used to modify the monitoring technique. Forexample, the thus-obtained information may be used to change (or add)threshold values in the foregoing algorithms/processes, or to determineif an alternative monitoring technique or combinations of monitoringtechniques should be used. In another example, if the thus-obtainedinformation indicates the pulse rate of second pulses, a dedicatedbandpass filter (e.g. centered on the thus-obtained pulse rate) may beoperated on the measurement signal/filtered measurementsignal/evaluation segment to further improve the input to the processfor obtaining timing information (cf. step 602 in FIG. 6) and/or theprocess for obtaining the parameter value based on the measurementsignal (cf. step 203/603 in FIGS. 2 and 9). In one embodiment, such abandpass filter is applied if the rates of first and second pulses arefound to differ by more than a certain limit, e.g. about 10%.

In another embodiment, the first pulse generator is selectivelycontrolled so as to reduce the flow rate through the fluid arrangement.By reducing the flow rate, it is possible to accept a longer responsetime of the monitoring process to a fault condition, while such a longerresponse time may serve to improve the precision of the monitoringprocess in detecting fault conditions.

Monitoring of an Extracorporeal Blood Flow Circuit

In the following, for the purpose of illustration only, animplementation of the first and second inventive concepts for monitoringthe integrity of a fluid connection is described in the context ofextracorporeal blood treatment. The following example involves acombination with the above-mentioned beating detection method. This isonly an example, and the monitoring process could be equally implementedwithout the beating detection method and/or in combination with any oneof the other monitoring techniques discussed above.

It should also be understood that the following implementation of thefirst and second inventive concepts, as well as the beating detectionmethod, is not limited to extracorporeal blood treatment, but isgenerally applicable for monitoring the integrity of a fluid connectionbetween first and second fluid containing systems.

FIG. 10 shows an example of an extracorporeal blood flow circuit 20 ofthe type which is used for dialysis. The extracorporeal blood flowcircuit 20 comprises components 1-14 to be described in the following.Thus, the extracorporeal blood flow circuit 20 comprises an accessdevice for blood extraction in the form of an arterial needle 1, and anarterial tube segment 2 which connects the arterial needle 1 to a bloodpump 3 which may be of peristaltic type, as indicated in FIG. 10. At theinlet of the pump there is a pressure sensor 4 a (hereafter referred toas arterial sensor) which measures the pressure before the pump in thearterial tube segment 2. The blood pump 3 forces the blood, via a tubesegment 5, to the blood-side of a dialyser 6. Many dialysis machines areadditionally provided with a pressure sensor 4 b that measures thepressure between the blood pump 3 and the dialyser 6. The blood is leadvia a tube segment 10 from the blood-side of the dialyser 6 to a venousdrip chamber or deaeration chamber 11 and from there back to the patientvia a venous tube segment 12 and an access device for bloodreintroduction in the form of a venous needle 14. A pressure sensor 4 c(hereafter referred to as venous sensor) is provided to measure thepressure on the venous side of the dialyser 6. In the illustratedexample, the pressure sensor 4 c measures the pressure in the venousdrip chamber. Both the arterial needle 1 and the venous needle 14 areconnected to the patient by means of a blood vessel access. The bloodvessel access may be of any suitable type, e.g. a fistula, aScribner-shunt, a graft, etc. Depending on the type of blood vesselaccess, other types of access devices may be used instead of needles,e.g. catheters.

As discussed by way of introduction, it may be vital to monitor theintegrity of the fluid connection to the blood vessel access withrespect to malfunction in the injection and/or extraction of bloodtherethrough. In many dialysis machines, one or more of said pressuredetectors 4 a-4 c are not present. However, there will be at least onevenous pressure sensor. The following description is focused onmonitoring the integrity of the fluid connection between the bloodvessel access and the venous needle based on a measurement signal fromthe venous pressure sensor. The monitoring process involves a so-calleddirect detection method, which may implement one of the first and secondinventive concepts, and its different embodiments, as discussed above.Thus, in relation to the general arrangement in FIG. 1, theextracorporeal blood flow circuit 20 corresponds to the first fluidcontaining system S1, the blood pump 3 (as well as any further pulsesource(s) within or associated with the extracorporeal blood flowcircuit 20, such as a dialysis solution pump, valves, etc) correspondsto the first pulse generator 3, the blood system of the patientcorresponds to the second fluid containing system S2, and the heart ofthe patient corresponds to the second pulse generator 3′.

In FIG. 10, a control unit 23 is provided, i.a., to control the bloodflow in the circuit 20 by controlling the revolution speed of the bloodpump 3. The extracorporeal blood flow circuit 20 and the control unit 23may form part of an apparatus for extracorporeal blood treatment, suchas a dialysis machine. Although not shown or discussed further it is tobe understood that such an apparatus performs many other functions, e.g.controlling the flow of dialysis fluid, controlling the temperature andcomposition of the dialysis fluid, etc.

Further, in FIG. 10, a surveillance/monitoring device 25 is configuredto monitor the integrity of the venous-side fluid connection between thepatient and the extracorporeal blood flow circuit 20, specifically bymonitoring the presence of a signal component originating from thepatient's heart in a blood pressure signal. Absence of such a signalcomponent is taken as an indication of a failure in the integrity of thefluid connection, and brings the device 25 to activate an alarm and/orstop the blood flow, e.g. by stopping the blood pump 3 and activating aclamping device 13 on tube segment 12. The surveillance device 25 is atleast connected to receive a measurement signal of the pressure sensor 4c. The device 25 may also be connected to pressure sensors 4 a, 4 b, aswell as any additional pressure sensors included in the extracorporealblood flow circuit 20. As indicated in FIG. 10, the device 25 may alsobe connected to the control unit 23. Alternatively or additionally, thedevice 25 may be connected to a measurement device 26 for indicating thefrequency and phase of the blood pump 3. The device 25 is tethered orwirelessly connected to a local or remote device 27 for generating anaudible/visual/tactile alarm or warning signal. The surveillance device25 and/or the alarm device 27 may alternatively be incorporated as partof a dialysis apparatus.

In FIG. 10, the surveillance device 25 comprises a data acquisition part28 for pre-processing the incoming signal(s), e.g. including an A/Dconverter with a required minimum sampling rate and resolution, one ormore signal amplifiers, one or more filters to remove undesiredcomponents of the incoming signal(s), such as offset, high frequencynoise and supply voltage disturbances.

In the examples given herein, the data acquisition part 28 comprises aDAQ card USB-6210 from National Instruments with a sampling rate of 1kHz and resolution of 16 bits, an operation amplifying circuit AD620from Analog Devices, a high-pass filter with a cut-off frequency of 0.03Hz (i.a., for removal of signal offset) together with a low-pass filterwith a cut-off frequency of 402 Hz (i.a., for removal of high frequencynoise). To obtain a short convergence time, a low-order filter is usedfor the high-pass filter. Furthermore, the data acquisition part 28 mayinclude an additional fixed band-pass filter with upper and lowercut-off frequencies of 0.5 Hz and 2.7 Hz, respectively, whichcorresponds to heart pulse rates between 30 and 160 beats per minute.This filter may be used to suppress disturbances outside the frequencyinterval of interest.

After the pre-processing in the data acquisition part 28, the signalfrom the pressure sensor 4 c is provided as input to a data analysispart 29, which executes the actual monitoring process. FIG. 11(a) showsan example of such a pre-processed pressure signal in the time domain,and FIG. 11(b) shows the corresponding power spectrum, i.e. the pressuresignal in the frequency domain. The power spectrum reveals that thedetected pressure signal contains a number of different frequencycomponents emanating from the blood pump 3. In the illustrated example,there is a frequency component at the base frequency (f₀) of the bloodpump (at 1.5 Hz in this example), as well as its harmonics 2f₀, 3f₀ and4f₀. The base frequency, also denoted pumping frequency in thefollowing, is the frequency of the pump strokes that generate pressurewaves in the extracorporeal blood flow circuit. For example, in aperistaltic pump of the type shown in FIG. 10, two pump strokes aregenerated for each full revolution of the rotor. FIG. 11(b) alsoindicates the presence of a frequency component at half the pumpingfrequency (0.5f₀) and harmonics thereof, in this example at least f₀,1.5f₀, 2f₀ and 2.5f₀. FIG. 11(b) also shows a heart signal (at 1.1 Hz)which in this example is approximately 40 times weaker than the bloodpump signal at the base frequency f₀.

FIG. 12 is a flow chart for a data analysis or monitoring processaccording to an embodiment of the present invention. The illustratedprocess implements a combination of detection methods to monitor theintegrity of the fluid connection between the extracorporeal blood flowcircuit 20 and the blood system of a human. One detection method(“direct detection”) involves using a time domain analysis for detectinga heart pulse in the pressure signal. Another detection method (“beatingdetection”) involves detecting an amplitude modulation (beating signal)in the pressure signal, the amplitude modulation being caused byinterference between pressure waves originating from the patient's heartand the blood pump. These detection methods will be described in furtherdetail below, but first the overall operation of the process will bebriefly outlined.

The monitoring process starts by inputting a signal segment of thepressure signal (step 401), as well as information on the base frequency(f₀) of the blood pump (step 402). This frequency information may beobtained from processing of the pressure signal itself. Alternatively,it may be obtained from a signal generated by a dedicated measurementdevice (cf. 26 in FIG. 10), or from a signal indicative of a set valueor actual value used by the control unit (cf. 23 in FIG. 10). It is tobe understood that step 402 need not be executed for every iteration ofthe monitoring process.

The direct detection method involves steps 403-405, in which the signalsegment is processed so as to remove first pulses originating from theblood pump, e.g. by blocking one or more of the frequency components(see 0.5f₀, f₀, 1.5f₀, 2f₀, 2.5f₀, 3f₀ and 4f₀ in FIG. 11) related tothe blood pump. Typically, step 403 (corresponding to step 202 in FIG.2) is designed to effectively “clean” the signal segment from allfrequency components emanating from the blood pump. In step 404(corresponding to step 203 in FIG. 2), the signal segment is analysed inthe time domain to identify any remaining signal pulse emanating fromthe patient's heart. If such a heart pulse is detected in step 405(corresponding to step 204 in FIG. 2), the monitoring is returned tostep 401, in which a new pressure signal segment is inputted forprocessing. As mentioned above, this new signal segment may or may notpartially overlap the preceding signal segment. If no heart component isdetected in step 405, the monitoring proceeds to beating detection. Thelack of a heart pulse may result from a malfunction of the venous-sidefluid connection, e.g. by the venous needle detaching from the bloodvessel access, or by the heart pulse being too weak to be detected.Alternatively, the heart beat frequency may essentially coincide withany of the frequency components of the blood pump, causing the heartpulse to be accidentally eliminated in the filtering step 403.

In an alternative implementation, the direct detection method steps403-405 correspond to steps 602-604 according to the second inventiveconcept discussed above in relation to FIG. 6.

In either implementation, the direct detection method may utilize timinginformation, which may be obtained as described above in relation to thesecond inventive concept.

The beating detection method involves steps 406-408, in which the signalsegment is processed so as to identify a beating signal caused byinterference between pressure waves originating from the heart and theblood pump, respectively. The beating signal is perceived as periodicvariations in signal amplitude with a frequency equal to the differencein frequency between these two pressure waves. Thus, instead ofsearching for the heart pulse itself in the pressure signal, the beatingdetection looks at indirect effects of the heart pulse on the pressuresignal in the time domain.

In step 406, the signal segment is processed to remove all frequenciesexcept for one or more selected frequency bands. Each such selectedfrequency band is a band surrounding only one of the frequencycomponents (see 0.5f₀, f₀, 1.5f₀, 2f₀, 2.5f₀, 3f₀ and 4f₀ in FIG. 11)related to the blood pump. This selective bandpass filtering may beeffected to facilitate the detection of the beating signal. The pressurewave from the heart is generally much smaller (typically 20-200 times)than the pressure wave from the blood pump, so a potential beating wavewill be weak and possibly difficult to detect. Typically, allfrequencies outside one such selected frequency band are removed fromthe signal segment, whereupon the resulting filtered signal segment isanalysed in the time domain for detection of a beating signal (step407). If the blood pump is known to produce a number of frequencycomponents (as shown in FIG. 11), step 406 results in a set of filteredsignal segments, each including only frequencies around one of thesefrequency components. These filtered signal segments may be generated inparallel and then analysed in step 407. Alternatively, filtered signalsegments may be generated in sequence, based on a given order of bloodpump frequency components. Each filtered signal segment may be passed onto step 407 for analysis before another filtered signal segment isgenerated, such that the generating of filtered signal segments isinterrupted as soon as a beating signal is detected.

In yet another embodiment, the heart pulse rate is known. In such asituation, step 406 may be limited to generating only one filteredsignal segment, which includes only frequencies around the frequencycomponent that lies closest to the known heart frequency. The heartpulse rate is suitably obtained in similar way as the timinginformation.

The selective bandpass filtering of step 406 may use a fixed width ofthe frequency band(s), which is set in view of a desired performance ofthe beating detection method, typically the maximum frequency spacingbetween a heart pulse and a pump frequency component that should resultin a beating signal. For example, the frequency bands used by thebeating detection method may be small compared to the spacing of thepump frequency components, if the beating detection method is used incombination with another detection method (e.g. the direct detectionmethod) which is capable of detecting presence/absence of a heart signalin specific frequency regions in between these frequency components. Inother situations, the frequency bands may have about the same totalwidth as the spacing of the pump frequency components, or the frequencybands of adjacent pump frequency components may even overlap. In anotherembodiment, the width of the frequency band(s) may be adaptively set asa function of a previously determined heart frequency. For example, thewidth may be reduced as the heart frequency approaches one of the pumpfrequency components. As mentioned above, the heart frequency may e.g.be obtained from a separate pulse rate meter, another pressure sensor,or in a preceding iteration of the monitoring process.

However, it is to be understood that the selective bandpass filteringaround different frequency components of the blood pump is included tofacilitate beating detection, but may be dispensed with.

If a beating signal is detected in step 408, the monitoring is returnedto step 401, in which a new pressure signal segment is inputted forprocessing. If no beating signal is detected in step 408, the monitoringproceeds to activate an alarm that indicates a malfunction, or at leasta warning that such a malfunction may have occurred (step 409).Concurrently with activating the alarm/warning, the process may proceedto step 410 in which the pumping frequency is changed, whereupon themonitoring process may return to step 401 to continue to monitor theintegrity of the fluid connection between the blood vessel access andthe venous needle. If a heart component/beating signal is discoveredduring subsequent iteration(s) of the monitoring process, thealarm/warning may be shut off. Alternatively, to minimize the number offalse alarms, the alarm/warning may be activated only if the monitoringprocess fails to detect the heart signal both before and after such achange in pumping frequency.

In one embodiment of step 410, the pump is kept operative, but itspumping frequency is changed. In one variant, the pumping frequency islowered in order to reduce the blood flow and thereby minimize any bloodloss caused by the potential malfunction that has been detected. Inanother variant, the pumping frequency is actively shifted such that itsfrequency components are non-coincident with its previous frequencycomponents. For example, the base frequency could be shifted by afraction of the spacing between the frequency components originatingfrom the pump. In the example of FIG. 11, this would mean a fraction of0.5f₀. Typically, the shift represents a reduction in the pumpingfrequency.

In another embodiment of step 410, the pump is shut-down (i.e. f₀=0) toremove the interference from the blood pump while also minimizing anyblood loss caused by the potential malfunction that has been detected.In a variant of such an embodiment, step 410 also involves identifyingthe frequency of the heart while the blood pump is shut-down, and thenre-starting the blood pump with a pumping frequency shifted from thethus-identified heart frequency. The heart frequency may be identifiedfrom the pressure signal, e.g. using the spectral signal analysis ofstep 404.

FIG. 13 is a block diagram of the data analysis part (cf. 29 in FIG. 10)which is configured to carry out the monitoring process shown in FIG.12. In the illustrated embodiment, the data analysis part includes astorage block 50, a pump frequency determination block 51, a directdetection block 52, a beating detection block 53, and switching blocks54, 55 for connecting the output of the direct detection block 52 andthe beating detection block 53 to an alarm device. Although not shown, acontrol block may be provided to synchronize the operation of the blocks50-55.

The data analysis part 29 may be implemented by software running on aprocessing device, such as a general- or special-purpose computer deviceor a programmed microprocessor. The storage block 50 may be a volatileor non-volatile memory of such a computer device, whereas the otherblocks 51-55 may be implemented by software instructions. However, it isconceivable that some or all blocks are fully or partially implementedby dedicated hardware, such as an FPGA, an ASIC, or an assembly ofdiscrete electronic components (resistors, capacitors, operationalamplifier, transistors, etc), as is well-known in the art.

The storage block 50 is operated to store the incoming pressure signalas a sequence of data samples. The other blocks 51-53 are then operatedto receive or retrieve segments of the stored pressure signal from thestorage block 50. The storage block 50 thus buffers the incomingpressure signal, allowing overlapping or non-overlapping signal segmentsto be individually processed and analysed. The storage block 50 may,e.g., be implemented as a plurality of linear buffers or as a circularbuffer.

Block 51 is configured to determine the frequency of the blood pumpbased on a signal segment. An example of an algorithm used by such ablock will be further described below.

Block 52 implements the direct detection steps 403-405 (FIG. 12), basedon an estimated pumping frequency provided by the pump frequencydetermination block 51. If the outcome of the determination step 405 isnegative, i.e. no heart component is found, switching block 54 isoperated to activate block 53. If a heart component is found, switchingblock 54 may be operated to provide a positive status indication to thealarm device, and a new signal segment may be received or retrieved byblocks 51, 52.

Block 53 implements the beating detection steps 406-408 (FIG. 12), againbased on the estimated pumping frequency. If the outcome ofdetermination step 408 is negative, i.e. no beating signal is detected,switching block 55 is operated to provide a negative status indicationto the alarm device, which issues an alarm. If a beating signal isfound, switching block 55 may be operated to provide a positive statusindication to the alarm device, and a new signal segment may be receivedor retrieved by the blocks 51, 52.

In FIG. 13, the data analysis part also includes an input 56 forreceiving a signal indicative of the pumping frequency (e.g. from themeasurement device 26 or the control unit 23 in FIG. 10). As discussedin relation to step 410 (FIG. 12), frequency information obtained fromthis signal may supplement or replace the frequency determined by block51.

FIG. 13 also indicates the provision of an input 57 for a measurementsignal indicative of the patient's heart frequency, e.g. to providetiming information to block 52 or to be used by block 53 when executingstep 406.

An exemplifying operation for each of the blocks 51-53 will now bedescribed, starting with the pump frequency determination block 51.

The pump frequency determination block 51 is configured to calculate apower spectrum from a pressure signal segment, and identify the basepumping frequency in the power spectrum. The power spectrum can becalculated in any known way, e.g. by operating a DFT (Discrete FourierTransform) or an FFT (Fast Fourier Transform) on the pressure signalsegment. The base pumping frequency may be identified as the frequencyof the largest peak in the power spectrum, or at least among one of thelargest peaks.

If the resolution of the power spectrum is low, special measures may beemployed to increase the accuracy of the estimated frequency. Theresolution is dependent on the sampling frequency f_(s) and the numberof samples N in the signal segment as f_(s)/N. In one example, signalsegments of 20 seconds are sampled at 10 Hz, with a resolution of 0.05Hz. This accuracy may be inadequate for the processing in the directdetection block 52 and/or beating detection block 53. To increase theaccuracy, the signal segment may be bandpass filtered in a narrow rangearound the estimated frequency obtained from the power spectrum,resulting in a comparatively noiseless and sinusoid-like signal segment.A precise estimation of the base frequency can then be obtained bydetermining the period of the filtered signal segment in the timedomain, e.g. by adapting a sinusoid to the filtered signal andidentifying the time difference between zero-crossings.

The direct detection block 52 may comprise components for cancelling thesignal pulses that emanate from the blood pump, and any furtherinterfering pulse sources (i.e. the “first pulses” discussed above inrelation to the first and second inventive concepts). Furthermore, thedirect detection block 52 may comprise components that obtain theaforesaid timing information, as well as components that carry out thetime domain analysis according to the first and/or second aspects foridentification of heart pulses in the pressure signal.

The beating detection block 53 is configured to filter the signalsegment with respect to a set of passbands, each containing onefrequency component of the blood pump. Each resulting filtered signalsegment is essentially a sinusoid. If the frequency of the heart lieswithin one of these passbands, then the corresponding filtered signalsegment will have a waveform not to be found in any of the otherfiltered signal segments.

FIG. 14(a) shows a 20 second signal segment which has been filtered witha narrow bandpass surrounding the base frequency of the blood pump at1.5029 Hz. The filtered signal also contains a heart pulse, which has afrequency shift of 0.037 Hz with respect to the base frequency. Therelative magnitude between the blood pump and heart pulse is 40:1. FIG.14(b) shows a corresponding filtered signal segment without a heartsignal. Although being very small, it is possible to distinguish adifference between the signal segments, where the presence of the heartcauses an overlying variation in signal amplitude in FIG. 14(a) which islacking in FIG. 14(b). FIGS. 15(a) and 15(b) are enlarged views of thesignal peaks in FIGS. 14(a) and 14(b), respectively, showing a cleardifference between the filtered signal segments with and without a heartpulse.

In one embodiment, the beating detection block 53 is configured todetect the beating signal based on an envelope obtained from thefiltered signal segment.

In one such variant, the beating detection block 53 obtains the envelopeby extracting an array of peak values from the signal segment. Theextracted peak values may be given by extracting signal values ofindividual peaks identified in the signal segment. To improve noiserobustness, each extracted peak value may instead be calculated as anaverage or sum of the signal values forming each peak in the signalsegment, e.g. including signal values within 10-25% of the peak value orwithin a given time range around the peak value. The obtained envelope(peak value array) is then processed for calculation of an evaluationparameter. FIGS. 16(a) and 16(b) show peak value arrays extracted fromFIGS. 15(a) and 15(b), respectively.

In another variant, block 53 obtains the envelope by applying a linear,time-invariant filter known as a Hilbert transformer to the signalsegment x. This operation results in a transformed signal segment {hacekover (x)}, which is a 90° phase-shifted version of the signal segment.The envelope b(n) can then be obtained from

b(n)=√{square root over (x²(n)+{hacek over (x)}²(n))}, with n being thedifferent positions in the signal segment.

For improved processing efficiency, block 53 may obtain an approximateenvelope {circumflex over (b)}(n) from the signal segment x based on therelation

${\hat{b}(n)} = {{{x(n)}} + {\frac{2}{\pi}{{{{x\left( {n + 1} \right)} - {x\left( {n - 1} \right)}}}.}}}$

The obtained envelope, be it approximate or not, is then processed forcalculation of an evaluation parameter.

In either variant, the obtained envelope may be low-pass filtered tofurther remove envelope noise, before being processed for calculation ofthe evaluation parameter.

In either variant, the resulting value of the evaluation parameter maybe compared to a threshold value for determining presence or absence ofa beating signal.

In one example, the evaluation parameter is the absolute sum ofderivatives of the values of the envelope, given by:

$\sum\limits_{n = 0}^{N - 1}\;{\left( {{b\left( {n + 1} \right)} - {b(n)}} \right)}$with b(n) being the envelope value at position n, and N being the numberof values in the envelope.

FIG. 17 illustrates a result of moving a 20 second window over a 5minute pressure signal, one second at the time, and calculating theabsolute sum of derivatives on an envelope obtained for each 20-secondsignal segment. The upper curve is calculated for filtered signalsegments containing a heart signal, and the lower curve is calculatedfor filtered signal segments without a heart signal. Clearly, athreshold value can be defined to distinguish between the presence andabsence of a heart signal.

The upper curve exhibits a waveform due to the fact that the signalsegment contains part of a full beating signal period. Thus, over time,the signal segments will contain different parts of the beating signal.Since the gradient is small around the peaks and valleys of the envelopeand larger therebetween, the calculated sum of derivatives will varycorrespondingly over time. It should be realized that, for a givenlength (time window) of the signal segment, the detectability of thegradients will decrease with decreasing frequency difference betweenheart and blood pump, since this lowers the beating frequency andflattens the envelope. A wider time window will improve thedetectability until the point where the amplitude of the beating becomessmaller than the noise.

In another example, the evaluation parameter is the variance of thevalues of the envelope. FIG. 18 is a plot corresponding to FIG. 17, butillustrating the variance as a function of time, with (upper) andwithout (lower) a heart signal. Clearly, a threshold value can bedefined to distinguish between the presence and absence of a heartsignal.

In yet another example, which may reduce influence of envelope noise,the evaluation parameter is an averaged sum of derivatives, e.g. givenby

$\sum\limits_{n = 1}^{N - 1}\;{{\frac{\left( {{b\left( {n + 1} \right)} - {b\left( {n - 1} \right)}} \right)}{2}}.}$

In another embodiment, the beating detection block 53 determines thepresence or absence of a beating signal based on pattern recognitionprocessing. For example, all or part of the signal segment or theenvelope may be matched against one or more predetermined signalpatterns that are representative of a beating signal. In one example,the obtained envelope (optionally low-pass filtered) may becross-correlated or otherwise convolved with each of a set of sinuswaves of different frequencies. Each cross-correlation/convolutionresults in a correlation curve, from which a maximum correlation valuecan be obtained. The resulting set of maximum correlation values maythen be compared to a threshold value for determining presence/absenceof a beating signal, where a high enough maximum correlation value maybe taken as an indication of such presence.

In an alternative implementation, the beating detection block 53operates on signal segments that are long in relation to the period ofthe beating signal, and processes these signal segments to detect thebeating signal in the frequency domain, e.g. by operating a Fouriertransformation on the envelope.

All of the above examples of determining presence of a beating signalmay involve the further step of assessing the reliability of thedetermined beating signal. This assessment may involve determining thebeating frequency of the beating signal and checking if this beatingfrequency is reasonable. Depending on how the beating signal isidentified, the beating frequency may be determined by processing theobtained envelope in the time/frequency domain, or by identifying thefrequency of the sinus wave that yields the maximum correlation value.The beating frequency may be checked in absolute terms and/or inrelation to one or more beating frequencies determined in precedingiterations of the monitoring process (FIG. 12), where large enoughdeviations from the preceding beating frequency/frequencies may be takenas an indication that the determined beating signal is unreliable. Theassessment may result in a reliability score that indicates thereliability of the determined beating signal. Alternatively oradditionally, the reliability assessment may include the step ofcontrolling the pump to change its pumping frequency and checking if acorresponding change occurs in the beating signal. For example, thepumping frequency may be shifted slightly, or the pump may beintermittently shut-down. The outcome of the reliability assessment mayaffect the execution of steps 409-410, e.g. whether an alarm/warning isactivated, whether further iterations of the monitoring process isrequired before activating the alarm/warning, whether the pumpingfrequency is to be changed, etc.

Tests have shown that different evaluation parameters may be preferablein different situations. For example, the use of variance may increasethe detectability when looking for a beating signal around one of theharmonics, whereas the use of absolute sum of derivatives or averagedsum of derivatives may be better when looking for a beating signalaround the base frequency. Pattern recognition may be resorted to whenother detection methods fail. Thus, the beating detection block 53 maybe configured to use one or any combination of these evaluationparameters.

FIG. 19 is an example of frequency and amplitude ranges in which a heartpulse is detectable using the beating detection block 53. The dottedlines indicate the frequency range of a normal heart, and the darkhorizontal bands indicate the frequencies at which a heart pulse couldbe detected in a system using a pumping frequency of 1.13 Hz. The fiverows of horizontal bands represent different relative magnitudes betweenthe blood pump and heart pulses, ranging from 20:1, 40:1, 60:1, 80:1 and100:1 from the bottom row to the top row.

The invention has mainly been described above with reference to a fewembodiments. However, as is readily appreciated by a person skilled inthe art, other embodiments than the ones disclosed above are equallypossible within the scope and spirit of the invention.

For example, the pressure signal may originate from any conceivable typeof pressure sensor, e.g. operating by resistive, capacitive, inductive,magnetic or optical sensing, and using one or more diaphragms, bellows,Bourdon tubes, piezo-electrical components, semiconductor components,strain gauges, resonant wires, etc.

Further, the illustrated embodiments are applicable for surveillance ofall types of extracorporeal blood flow circuits in which blood is takenfrom a patient's circulation to have a process applied to it before itis returned to the circulation. Such blood flow circuits includehemodialysis, hemofiltration, hemodiafiltration, plasmapheresis,apheresis, extracorporeal membrane oxygenation, assisted bloodcirculation, and extracorporeal liver support/dialysis.

Further, the inventive monitoring techniques are applicable to any typeof pumping device that generates pressure pulses in the first fluidcontaining system, not only rotary peristaltic pumps as disclosed above,but also other types of positive displacement pumps, such as linearperistaltic pumps, diaphragm pumps, as well as centrifugal pumps.

Still further, the inventive monitoring techniques are applicable alsofor monitoring the integrity of the fluid connection between the bloodvessel access and the arterial needle based on a measurement signal fromone or more arterial pressure sensors. Such a monitoring technique mayprovide a faster detection of malfunction than the conventional airdetector, and more reliable detection of malfunction than conventionalcomparison of average pressure levels to threshold values. In such anapplication, the aforesaid reference signal may be derived from one ormore venous pressure sensors in the extracorporeal blood flow circuit.

Also, it is to be understood that the monitoring technique is equallyapplicable to single-needle dialysis.

The inventive monitoring techniques are also applicable when themeasurement signal originates from a pressure sensor arranged to sensethe pressure in the human blood system. In such an embodiment, the firstfluid containing system (S1) is the human blood system, the second fluidcontaining system (S2) is the extracorporeal blood flow circuit, and thefluid connection (C) may be formed by a connection between an accessdevice and a blood vessel access. The first pulses thus originate fromthe human heart, and the second pulses originate from the pumping devicein the extracorporeal blood flow circuit (and/or any other pulsegenerator within or associated with the extracorporeal blood flowcircuit), and the integrity of the fluid connection is determined byapplying the first and/or second inventive concepts to detect thepresence/absence of the second pulses in the measurement signal.

Furthermore, the monitoring process is not limited to digital signalprocessing. FIG. 20 illustrates an exemplary combination of analogdevices for detection of a beating component in a pressure signal. Theindividual devices are known per se, and alternative implementations arereadily available to the skilled person. The exemplary combination ofanalog devices includes a bandpass filter 151 which is adapted to filteran incoming pressure signal to isolate a signal component at the basefrequency (f₀) of the pumping device. A frequency multiplier 152 isarranged to receive the filtered pressure signal and is controllable togenerate a corresponding output signal at a selected multiple (0.5, 1,2.5, 3 etc) of the base frequency. The output signal from the multiplier152 is input as a control signal to a controllable bandpass filter 153,which is adapted to receive and filter the incoming pressure signal. Thefilter 153 is thereby controlled to process the pressure signal byremoving all frequencies except for a frequency band around thefrequency of the control signal from the multiplier 152 (cf. step 406 inFIG. 12). The processed pressure signal is input to a peak detector 154which thereby generates an envelope signal, which in turn is fed to ahigh-pass filter 155 which removes any DC component from the envelopesignal. Optionally, a low-pass filter (not shown) may be included toremove high-frequency noise from the envelope signal. Finally, theenvelope signal is received by an amplitude detector 156 which isadapted to determine presence/absence of a beating signal. The amplitudedetector may include, in sequence, a full wave rectifier 156 a, alow-pass filter 156 b and a comparator 156 c which is fed with areference signal. If the amplitude of the input signal to the comparator156 c exceeds the reference signal, the comparator 156 c may output asignal indicating presence of a beating signal, otherwise not, or viceversa.

The above-described inventive concepts may also be applicable tomonitoring the integrity of fluid connections for transferring otherliquids than blood. Likewise, the fluid connections need not be providedin relation to a human, but could be provided in relation to any othertype of fluid containing system.

In one example, the fluid connection is provided between a bloodprocessing circuit and a container/machine, wherein blood is pumped fromone container/machine through a blood processing device in the bloodprocessing circuit and back to the container/machine, or to anothercontainer/machine downstream of the blood processing device. The bloodprocessing device could be any known device configured to modify and/oranalyse the blood.

In a further example, the fluid connection is provided between adialyser and a reprocessing system, which reprocesses the dialyser bypumping water, optionally together with suitable chemicals through thedialyser. An example of a dialyser reprocessing system is known fromUS2005/0051472.

In another example, the fluid connection is provided between a dialysatesupply and a dialysate regeneration system, which circulates dialysatefrom the dialysate supply through a dialysate regeneration device andback to the supply. An example of a dialysate regeneration device isknown from WO 05/062973.

In yet another example, the fluid connection is provided in anarrangement for priming an extracorporeal blood flow circuit by pumpinga priming fluid from a supply via the blood flow circuit to a dialyser.The priming fluid may e.g. be dialysis solution, saline, purified water,etc.

In a still further example, the fluid connection is provided in anarrangement for cleaning and disinfecting the dialysis solution flowpath of a dialysis machine, which pumps a cleaning fluid via a flow pathto a dialyser/dialyser tubing. The cleaning fluid may e.g. be hot water,a chemical solution, etc.

In a further example, the fluid connection is provided in an arrangementfor purifying water, which pumps water from a supply through a purifyingdevice. The purifying device may use any known water purificationtechnique, e.g. reverse osmosis, deionization or carbon absorption.

In another example, the fluid connection is provided in an arrangementfor providing purified water to a dialysis machine, e.g. to be used inthe preparation of dialysis solution therein.

In all of these examples, and in other applications related to medicaltreatment of human or animal patients, it may be vital to monitor theintegrity of the fluid connection. Such monitoring can be accomplishedaccording to the inventive concepts disclosed herein.

The invention claimed is:
 1. A method for monitoring the integrity of afluid connection between first and second fluid containing systems basedon at least one time-dependent measurement signal from at least onepressure sensor in the first fluid containing system, wherein the firstfluid containing system is an extracorporeal blood flow circuitcomprising an arterial access device, a blood processing device, avenous access device and a first pulse generator, and the second fluidcontaining system is a human blood system comprising a blood vesselaccess and a second pulse generator, wherein: the arterial access deviceis for connecting to the human blood system, the venous access device isconnected to the blood vessel access to form the fluid connection, thefirst pulse generator is a pumping device arranged in the extracorporealblood flow circuit to pump blood from the arterial access device throughthe blood processing device to the venous access device, and the atleast one pressure sensor is arranged to detect first pulses originatingfrom the first pulse generator and second pulses originating from thesecond pulse generator, said method comprising: receiving, at aprocessor, said at least one time-dependent measurement signal from theat least one pressure sensor; generating, by the processor, atime-dependent monitoring signal based on said at least one-timedependent measurement signal in which the first pulses are eliminated,said generating including (i) filtering said at least one time dependentmeasurement signal to remove the first pulses, (ii) deriving, based ontiming information indicative of the timing of the second pulses in saidat least one time-dependent measurement signal, a set of signal segmentsin the at least one time-dependent measurement signal after filteringthe at least one time-dependent measurement signal to remove the firstpulses, and (iii) aligning and adding the signal segments, based on thetiming information, to generate said monitoring signal; calculating, bythe processor, a parameter value based on signal values within a timewindow in the time-dependent monitoring signal, the parameter valuerepresenting a distribution of the signal values; and determining, bythe processor, the integrity of the fluid connection based at leastpartly on the parameter value.
 2. The method of claim 1, wherein saidcalculating comprises: calculating the parameter value as a statisticaldispersion measure of the signal values within the time window.
 3. Themethod of claim 2, wherein the statistical dispersion measure includesat least one of: a standard deviation, a variance, a coefficient ofvariation, a sum of differences, an energy, a power, a sum of absolutedeviations from an average value, and an average of absolute differencesfrom an average value.
 4. The method of claim 1, wherein saidcalculating includes matching the signal values within the time windowto a predicted temporal signal profile of the second pulses, and whereinthe parameter value is a correlation value resulting from said matching.5. The method of claim 1, wherein said calculating includes matching thesignal values within the time window to a predicted temporal signalprofile of the second pulses, and wherein said calculating comprises:calculating a cross-correlation between the signal values within thetime window and the predicted temporal signal profile; and identifying amaximum correlation value in the cross-correlation; wherein saiddetermining comprises: comparing the maximum correlation value to athreshold value.
 6. The method of claim 5, wherein said calculatingcomprises: obtaining a time point of the maximum correlation value, andvalidating the maximum correlation value by comparing the time point toa predicted time point.
 7. The method of claim 1, wherein saidcalculating includes matching the signal values within the time windowto a predicted temporal signal profile of the second pulses, and furthercomprising the step of obtaining a reference pressure signal from areference sensor in the first fluid containing system, wherein thereference sensor is arranged to detect said second pulses even if thefluid connection is compromised, and calculating the predicted temporalsignal profile based on the reference pressure signal.
 8. The method ofclaim 7, further comprising the steps of calculating a magnitude valueindicative of a magnitude of the second pulses in the reference pressuresignal, and comparing the magnitude value to a limit, wherein the stepof calculating the predicted temporal signal profile based on thereference pressure signal is conditioned upon said comparing of themagnitude value to the limit.
 9. The method of claim 7, wherein the stepof calculating the predicted temporal signal profile comprises adjustingfor a difference in transit time between the reference sensor and saidat least one pressure sensor.
 10. The method of claim 9, wherein saiddifference in transit time is given by a predefined value.
 11. Themethod of claim 9, wherein said difference in transit time is calculatedbased on a difference in fluid pressure between the location of thereference sensor and said at least one pressure sensor.
 12. The methodof claim 1, wherein the time window is selected so as to contain atleast one second pulse originating from the second pulse generator. 13.The method of claim 12, wherein the length of the time window is chosento exceed a maximum pulse repetition interval of the second pulsegenerator.
 14. The method of claim 12, wherein the time window is chosenbased on timing information indicative of the timing of the secondpulses in said at least one time-dependent measurement signal.
 15. Themethod of claim 14, wherein the timing information is obtained from apulse sensor coupled to the second fluid containing system.
 16. Themethod of claim 14, wherein the timing information is based on therelative timing of previously detected second pulses in thetime-dependent measurement signal.
 17. The method of claim 14, whereinthe at least one time dependent measurement signal comprises at leastone venous measurement signal derived from at least one venous pressuresensor located downstream of the pumping device, and at least onearterial measurement signal derived from at least one arterial pressuresensor located upstream of the pumping device, and wherein themonitoring signal is generated based on said at least one venousmeasurement signal, said method comprising: identifying at least onesecond pulse originating from the second pulse generator in said atleast one arterial measurement signal; and calculating the timinginformation from the at least one identified second pulse.
 18. Themethod of claim 14, further comprising: intermittently turning off thefirst pulse generator; identifying at least one second pulse originatingfrom the second pulse generator in said at least one time-dependentmeasurement signal; and calculating the timing information from theidentified second pulse.
 19. The method of claim 14, further comprising:identifying a set of candidate second pulses based on said at least onetime-dependent measurement signal; deriving a sequence of candidate timepoints based on the set of candidate second pulses; validating thesequence of candidate time points against a temporal criterion; andcalculating the timing information as a function of the validatedsequence of candidate time points.
 20. The method of claim 1, whereinsaid calculating comprises: identifying a candidate second pulse in themonitoring signal and a corresponding candidate time point; andvalidating the candidate second pulse based on the candidate time pointin relation to timing information indicative of the timing of the secondpulses in said at least one time-dependent measurement signal.
 21. Anon-transitory computer readable storage medium comprising instructionsfor causing a computer to perform the method of claim
 1. 22. A devicefor monitoring the integrity of a fluid connection between anextracorporeal blood flow circuit and a human blood system wherein theextracorporeal blood flow circuit comprises an arterial access deviceconnecting to the human blood system, a blood processing device, avenous access device, and a first pulse generator, and the human bloodsystem comprises a blood vessel access and a second pulse generator,wherein: the venous access device is configured to be connected to theblood vessel access to form the fluid connection, the first pulsegenerator is a pumping device configured to be arranged in theextracorporeal blood flow circuit to pump blood from the arterial accessdevice through the blood processing device to the venous access device,and at least one pressure sensor configured to detect first pulsesoriginating from the first pulse generator and second pulses originatingfrom the second pulse generator, said device comprising: an input for atleast one time-dependent measurement signal from the at least onepressure sensor in the extracorporeal blood flow circuit; and a signalprocessor connected to said input, said signal processor comprising aprocessing module configured to generate, based on said at least onetime-dependent measurement signal, a time-dependent monitoring signal inwhich the first pulses are eliminated, and to calculate a parametervalue based on signal values within a time window in the monitoringsignal, the parameter value representing a distribution of the signalvalues, said signal processor being configured to determine theintegrity of the fluid connection based at least partly on the parametervalue, wherein the processing module generates the monitoring signal by(i) filtering said at least one time dependent measurement signal toremove the first pulses, (ii) deriving, based on timing informationindicative of the timing of the second pulses in said at least onetime-dependent measurement signal, a set of signal segments in the atleast one time-dependent measurement signal after filtering the at leastone time-dependent measurement signal to remove the first pulses, and(iii) aligning and adding the signal segments, based on the timinginformation, to generate said monitoring signal.
 23. A device formonitoring the integrity of a fluid connection between an extracorporealblood flow circuit and a human blood system, wherein the extracorporealblood flow circuit comprises an arterial access device connecting to thehuman blood system, a blood processing device, a venous access device,and a first pulse generator, and the human blood system comprises ablood vessel access and a second pulse generator, wherein: the venousaccess device is configured to be connected to the blood vessel accessto form the fluid connection, the first pulse generator is a pumpingdevice configured to be arranged in the extracorporeal blood flowcircuit to pump blood from the arterial access device through the bloodprocessing device to the venous access device, and at least one pressuresensor configured to detect first pulses originating from the firstpulse generator and second pulses originating from the second pulsegenerator, said device comprising: means for receiving said at least onetime dependent measurement signal; means for generating, based on saidat least one time-dependent measurement signal, a time-dependentmonitoring signal in which the first pulses are eliminated, wherein saidmonitoring signal is generated by (i) filtering said at least one timedependent measurement signal to remove the first pulses, (ii) deriving,based on timing information indicative of the timing of the secondpulses in said at least one time-dependent measurement signal, a set ofsignal segments in the at least one time-dependent measurement signalafter filtering the at least one time-dependent measurement signal toremove the first pulses, and (iii) aligning and adding the signalsegments, based on the timing information, to generate said monitoringsignal; means for calculating a parameter value based on signal valueswithin a time window in the monitoring signal, the parameter valuerepresenting a distribution of the signal values; and means fordetermining the integrity of the fluid connection based at least partlyon the parameter value.
 24. A method for monitoring the integrity of afluid connection between first and second fluid containing systems basedon at least one time-dependent measurement signal from at least onepressure sensor in the first fluid containing system, wherein the firstfluid containing system is an extracorporeal blood flow circuitcomprising an arterial access device, a blood processing device, avenous access device, and a first pulse generator, and the second fluidcontaining system is a human blood system comprising a blood vesselaccess and a second pulse generator, wherein: the arterial access deviceis for connecting to the human blood system, the venous access device isconnected to the blood vessel access to form the fluid connection, thefirst pulse generator is a pumping device arranged in the extracorporealblood flow circuit to pump blood from the arterial access device throughthe blood processing device to the venous access device, and the atleast one pressure sensor is arranged to detect first pulses originatingfrom the first pulse generator and second pulses originating from thesecond pulse generator, said method comprising: receiving, by aprocessor, said at least one time-dependent measurement signal from theat least one pressure sensor; obtaining by the processor, timinginformation indicative of a predicted timing of the second pulses insaid at least one time-dependent measurement signal; processing, by theprocessor, said at least one time-dependent measurement signal based onthe timing information, to calculate a parameter value indicative ofpresence or absence of the second pulses; and determining, by theprocessor, the integrity of the fluid connection based at least partlyon the parameter value.
 25. The method of claim 24, wherein saidprocessing comprises: locating a time window in the measurement signal,or a monitoring signal obtained from the measurement signal, based onthe timing information; and calculating the parameter value based on thesignal values within said time window.
 26. The method of claim 25,wherein said processing further comprises: selecting the length of thetime window based on the timing information.
 27. The method of claim 24,wherein said processing comprises: generating a time-dependentmonitoring signal by filtering said at least one time-dependentmeasurement signal to remove the first pulses; wherein the parametervalue is calculated based on the monitoring signal.
 28. The method ofclaim 27, wherein said generating further comprises: selecting a set ofsignal segments in the at least one time-dependent measurement signalafter filtering the at least one time-dependent measurement signal toremove the first pulses; and aligning and adding the signal segments,based on the timing information, to generate the monitoring signal. 29.The method of claim 27, wherein said calculating comprises: identifyinga candidate second pulse in the monitoring signal and a correspondingcandidate time point; and validating the candidate second pulse based onthe candidate time point in relation to the timing information.
 30. Themethod of claim 24, wherein the timing information is obtained from apulse sensor coupled to the second fluid containing system.
 31. Themethod of claim 24, wherein the timing information is based on therelative timing of previously detected second pulses in the timedependent measurement signal.
 32. The method of claim 24, furthercomprising the step of obtaining a reference pressure signal from areference sensor in the first fluid containing system, wherein thereference sensor is arranged to detect said second pulses even if thefluid connection is compromised, and wherein said step of obtaining thetiming information comprises: identifying at least one second pulse inthe reference pressure signal and obtaining an estimated difference inarrival time between the reference sensor and said at least one pressuresensor.
 33. The method of claim 32, wherein the estimated difference inarrival time is given by a predefined value.
 34. The method of claim 32,wherein the estimated difference in arrival time is calculated based ona difference in fluid pressure between the location of the referencesensor and said at least one pressure sensor.
 35. The method of claim32, further comprising the steps of calculating a magnitude valueindicative of the magnitude of said at least one second pulse in thereference pressure signal, and comparing the magnitude value to a limit,wherein the step of obtaining an estimated difference in arrival time isconditioned upon said comparing of the magnitude value to the limit. 36.The method of claim 24, wherein at least one time-dependent measurementsignal comprises at least one venous measurement signal derived from atleast one venous pressure sensor located downstream of the pumpingdevice, and at least one arterial measurement signal derived from atleast one arterial pressure sensor located upstream of the pumpingdevice, and wherein the monitoring signal is generated based on said atleast one venous measurement signal, said method comprising: identifyingat least one second pulse originating from the second pulse generator insaid at least one arterial measurement signal; and calculating thetiming information from the at least one identified second pulse. 37.The method of claim 24, further comprising: turning off the first pulsegenerator; identifying at least one second pulse originating from thesecond pulse generator in said at least one time-dependent measurementsignal; and calculating the timing information from the at least oneidentified second pulse.
 38. The method of claim 24, further comprising:identifying a set of candidate second pulses based on said at least onetime-dependent measurement signal; deriving a sequence of candidate timepoints based on the set of candidate second pulses; validating thesequence of candidate time points against a temporal criterion; andcalculating the timing information as a function of the validatedsequence of candidate time points.
 39. The method of claim 24, whereinsaid obtaining further comprises: identifying a set of candidate secondpulses based on said at least one time-dependent measurement signal;deriving a sequence of candidate time points based on the set ofcandidate second pulses; generating a set of validated candidate secondpulses by validating the sequence of candidate time points against atemporal criterion; wherein said processing comprises: calculating a setof average representations, each average representation being formed byaligning and adding signal segments of said at least one time-dependentmeasurement signal that correspond to a unique combination of validatedcandidate second pulses; and calculating the parameter value for each ofsaid average representations; and wherein said determining comprisescomparing a maximum parameter value to a threshold value.
 40. The methodof claim 24, wherein the parameter value represents a distribution ofsignal values.
 41. A non-transitory computer readable storage mediumcomprising instructions for causing a computer to perform the method ofclaim
 24. 42. A device for monitoring the integrity of a fluidconnection between an extracorporeal blood flow circuit and a humanblood system, wherein the extracorporeal blood flow circuit comprises anarterial access device for connecting to the human blood system, a bloodprocessing device, a venous access device, and a first pulse generator,and the human blood system comprises a blood vessel access and a secondpulse generator, wherein: the venous access device is configured to beconnected to the blood vessel access to form the fluid connection, thefirst pulse generator is a pumping device configured to be arranged inthe extracorporeal blood flow circuit to pump blood from the arterialaccess device through the blood processing device to the venous accessdevice, and at least one pressure sensor configured to detect firstpulses originating from the first pulse generator and second pulsesoriginating from the second pulse generator, said device comprising: aninput for said at least one time-dependent measurement signal; and asignal processor connected to said input and comprising a processingmodule configured to obtain timing information indicative of a predictedtiming of the second pulses in said at least one time-dependentmeasurement signal, and to process said at least one time-dependentmeasurement signal based on the timing information so as to generate aparameter value indicative of presence or absence of the second pulses,said signal processor being configured to determine the integrity of thefluid connection based at least partly on the parameter value.
 43. Adevice for monitoring the integrity of a fluid connection between anextracorporeal blood flow circuit and a human blood system, wherein theextracorporeal blood flow circuit comprises an arterial access devicefor connecting to the human blood system, a blood processing device, avenous access device, and a first pulse generator, and the human bloodsystem comprises a blood vessel access and a second pulse generator,wherein: the venous access device is configured to be connected to theblood vessel access to form the fluid connection, the first pulsegenerator is a pumping device configured to be arranged in theextracorporeal blood flow circuit to pump blood from the arterial accessdevice through the blood processing device to the venous access device,and at least one pressure sensor is configured to detect first pulsesoriginating from the first pulse generator and second pulses originatingfrom the second pulse generator, said device comprising: means forreceiving said at least one time-dependent measurement signal; means forobtaining timing information indicative of a predicted timing of thesecond pulses in said at least one time-dependent measurement signal;means for processing said at least one time-dependent measurement signalbased on the timing information, to generate a parameter valueindicative of presence or absence of the second pulses; and means fordetermining the integrity of the fluid connection based at least partlyon the parameter value.